Combination therapy

ABSTRACT

The present invention relates to methods for treating and/or preventing metabolic diseases comprising the combined administration of a GLP-1 receptor agonist and a DPP-4 inhibitor.

The present invention relates to methods for treating and/or preventingmetabolic diseases, especially type 2 diabetes mellitus, obesity and/orconditions related thereto (e.g. diabetic complications) comprising thecombined administration of a GLP-1 receptor agonist (e.g. exogenousGLP-1 or a GLP-1 analogue) and a certain DPP-4 inhibitor, topharmaceutical compositions and combinations comprising such activecomponents, and to certain therapeutic uses thereof.

Further, the present invention relates to a method for reducing andmaintaining body weight and/or body fat in a patient in need thereof,such as e.g. in an overweight or obesity patient with or withoutdiabetes (particularly type 2 diabetes patient being obese oroverweight), comprising the combined (e.g. separate, simultaneous orsequential) administration of a GLP-1 receptor agonist (e.g. GLP-1 orGLP-1 analogue) and a certain DPP-4 inhibitor; preferably said methodcomprising the sequential administration of a GLP-1 receptor agonistfollowed by a certain DPP-4 inhibitor.

Furthermore, the present invention relates to a method for reducing andmaintaining body weight and/or body fat in a patient in need thereof,such as e.g. in an overweight or obesity patient with or withoutdiabetes (particularly type 2 diabetes patient being obese oroverweight), comprising i) inducing body weight loss (e.g. byadministering an effective amount of a GLP-1 receptor agonist to thepatient) and ii.) administering an effective amount of a certain DPP-4inhibitor to the patient.

Moreover, the present invention relates to a certain DPP-4 inhibitor foruse in preventing of body weight and/or body fat gain or controlling,stabilizing or maintaining a reduced body weight and/or body fatfollowed discontinuation of weight reducing treatment (such as e.g.diet, exercise and/or treatment with an anti-obesity or body weightreducing agent), particularly after discontinuation of treatment with aGLP-1 receptor agonist.

Further, the present invention relates to a certain DPP-4 inhibitor foruse in delaying body weight and/or body fat gain and/or maintainingreduction in body weight and/or body fat in a subject (particularly anobesity patient with or without diabetes), particularly subsequent tocessation of or withdrawn from body weight reducing and/or fat reducingtreatment.

Further, the present invention relates to a certain DPP-4 inhibitor foruse in a method of delaying body weight and/or body fat gain and/ormaintaining body weight and/or body fat loss induced by treatment with aGLP-1 receptor agonist in a subject, said method comprising cessation ofGLP-1 receptor agonist treatment and transferring the subject from GLP-1receptor agonist to DPP-4 inhibitor treatment.

Furthermore, the present invention relates to a DPP-4 inhibitor for usein reducing, maintaining loss of or delaying increase of body weightand/or body fat in a subject actively putting on weight.

Yet furthermore, the present invention relates to a DPP-4 inhibitor foruse in reducing, maintaining loss of or delaying increase of body weightand/or body fat in a subject being in condition of actively putting onweight and/or increasing body weight through the deposition of fat, suchas e.g. after withdrawing a weight loss treatment or under a treatmentassociated with weight gain (e.g. through the action of sulphonylureas,glinides, insulin and/or thiazolidinediones, the use of which isassociated with weight gain).

Further, the present invention relates to a certain DPP-4 inhibitor foruse in reducing intra-myocellular fat and/or hepatic fat in a patient inneed thereof, such as e.g. in an overweight or obesity patient with orwithout diabetes (particularly type 2 diabetes patient being obese oroverweight).

Further, the present invention relates to a DPP-4 inhibitor for use inachieving a reduction in the dose of GLP-1 receptor agonist medication,e.g. required for effective therapy of metabolic diseases (such as e.g.type 2 diabetes mellitus, obesity and/or conditions related thereto(e.g. diabetic complications)), e.g. in an overweight or obesity patientwith or without diabetes (particularly type 2 diabetes patient beingobese or overweight).

Moreover, the present invention relates to a certain DPP-4 inhibitor foruse in treating, preventing or reducing the risk of skin necrosis,particularly associated with or induced by infusions or injections, e.g.of a GLP-1 receptor agonist, insulin or insulin analogue or other drugsadministered subcutaneously and/or via needle or syringe, typicallypierced through the skin.

Further, the present invention relates to the DPP-4 inhibitors and/orGLP-1 receptor agonists, each as defined herein, for use in thecombination therapies as described herein.

Type 2 diabetes mellitus is a common chronic and progressive diseasearising from a complex pathophysiology involving the dual endocrineeffects of insulin resistance and impaired insulin secretion with theconsequence not meeting the required demands to maintain plasma glucoselevels in the normal range. This leads to chronic hyperglycaemia and itsassociated micro- and macrovascular complications or chronic damages,such as e.g. diabetic nephropathy, retinopathy or neuropathy, ormacrovascular (e.g. cardio- or cerebro-vascular) complications. Thevascular disease component plays a significant role, but is not the onlyfactor in the spectrum of diabetes associated disorders. The highfrequency of complications leads to a significant reduction of lifeexpectancy. Diabetes is currently the most frequent cause of adult-onsetloss of vision, renal failure, and amputation in the IndustrialisedWorld because of diabetes induced complications and is associated with atwo to five fold increase in cardiovascular disease risk.

Furthermore, diabetes (particularly type 2 diabetes) is often coexistentand interrelated with obesity and these two conditions together impose aparticularly complex therapeutic challenge. Because of the effects ofobesity on insulin resistance, weight loss and its maintainance is animportant therapeutic objective in overweight or obese individuals withprediabetes, metabolic syndrome or diabetes. Studies have beendemonstrated that weight reduction in subjects with type 2 diabetes isassociated with descreased insulin resistance, improved measures ofglycemia and lipemia, and reduced blood pressure. Maintainance of weightreduction over longer term is considered to improve glycemic control andprevent diabetic complications (e.g. reduction of risk forcardiovascular diseases or events). Thus, weight loss is recommended forall overweight or obese indivuduals who have or are at risk fordiabetes. However, obese patients with type 2 diabetes have much greaterdifficulty losing weight and maintain the reduced weight than thegeneral non-diabetic population.

Overweight may be defined as the condition wherein the individual has abody mass index (BMI) greater than or 25 kg/m² and less than 30 kg/m².The terms “overweight” and “pre-obese” are used interchangeably.

Obesity may be defined as the condition wherein the individual has a BMIequal to or greater than 30 kg/m². According to a WHO definition theterm obesity may be categorized as follows: class I obesity is thecondition wherein the BMI is equal to or greater than 30 kg/m² but lowerthan 35 kg/m²; class II obesity is the condition wherein the BMI isequal to or greater than 35 kg/m² but lower than 40 kg/m²; class IIIobesity is the condition wherein the BMI is equal to or greater than 40kg/m². Obesity may include e.g. visceral or abdominal obesity.

Visceral obesity may be defined as the condition wherein a waist-to-hipratio of greater than or equal to 1.0 in men and 0.8 in women ismeasured. It defines the risk for insulin resistance and the developmentof pre-diabetes.

Abdominal obesity may usually be defined as the condition wherein thewaist circumference is >40 inches or 102 cm in men, and is >35 inches or94 cm in women. With regard to a Japanese ethnicity or Japanese patientsabdominal obesity may be defined as waist circumference≧85 cm in men and≧90 cm in women (see e.g. investigating committee for the diagnosis ofmetabolic syndrome in Japan).

Diabetes patients within the meaning of this invention may includepatients having obesity or overweight.

Obesity patients within the meaning of this invention may include, inone embodiment, patients with diabetes (particularly having type 2diabetes).

Obesity patients within the meaning of this invention may include, inanother embodiment, patients without diabetes (particularly without type1 or type 2 diabetes).

The treatment of type 2 diabetes typically begins with diet andexercise, followed by oral antidiabetic monotherapy, and althoughconventional monotherapy may initially control blood glucose in somepatients, it is however associated with a high secondary failure rate.The limitations of single-agent therapy for maintaining glycemic controlmay be overcome, at least in some patients, and for a limited period oftime by combining multiple drugs to achieve reductions in blood glucosethat cannot be sustained during long-term therapy with single agents.Available data support the conclusion that in most patients with type 2diabetes current monotherapy will fail and treatment with multiple drugswill be required. But, because type 2 diabetes is a progressive disease,even patients with good initial responses to conventional combinationtherapy will eventually require an increase of the dosage or furthertreatment with insulin because the blood glucose level is very difficultto maintain stable for a long period of time. Although existingcombination therapy has the potential to enhance glycemic control, it isnot without limitations (especially with regard to long term efficacy).Further, traditional therapies may show an increased risk for sideeffects, such as hypoglycemia or weight gain, which may compromise theirefficacy and acceptability.

Thus, for many patients, these existing drug therapies result inprogressive deterioriation in metabolic control despite treatment and donot sufficiently control metabolic status especially over long-term andthus fail to achieve and to maintain glycemic control in advanced orlate stage type 2 diabetes, including diabetes with inadequate glycemiccontrol despite conventional oral or non-oral antidiabetic medication.

Therefore, although intensive treatment of hyperglycemia can reduce theincidence of chronic damages, many patients with type 2 diabetes remaininadequately treated, partly because of limitations in long termefficacy, tolerability and dosing inconvenience of conventionalantihyperglycemic therapies.

In addition, obesity, overweight or weight gain (e.g. as side or adverseeffect of some conventional antidiabetic medications) furthercomplicates the treatment of diabetes and its micorvascular ormacrovascular complications.

This high incidence of therapeutic failure is a major contributor to thehigh rate of long-term hyperglycemia-associated complications or chronicdamages (including micro- and makrovascular complications such as e.g.diabetic nephrophathy, retinopathy or neuropathy, or cardiovascularcomplications) in patients with type 2 diabetes.

Oral antidiabetic drugs conventionally used in therapy (such as e.g.first- or second-line, and/or mono- or (initial or add-on) combinationtherapy) include, without being restricted thereto, metformin,sulphonylureas, thiazolidinediones, glinides and α-glucosidaseinhibitors.

Non-oral (typically injected) antidiabetic drugs conventionally used intherapy (such as e.g. first- or second-line, and/or mono- or (initial oradd-on) combination therapy) include, without being restricted thereto,GLP-1 or GLP-1 analogues, and insulin or insulin analogues.

However, the use of these conventional antidiabetic or antihyperglycemicagents can be associated with various adverse effects. For example,metformin can be associated with lactic acidosis or gastrointestinalside effects; sulfonylureas, glinides and insulin or insulin analoguescan be associated with hypoglycemia and weight gain; thiazolidinedionescan be associated with edema, bone fracture, weight gain and heartfailure/cardiac effects; and alpha-glucosidase blockers and GLP-1 orGLP-1 analogues can be associated with gastrointestinal adverse effects(e.g. dyspepsia, flatulence or diarrhea, or nausea or vomiting) and,most seriously (but rare), pancreatitis.

Therefore, it remains a need in the art to provide efficacious, safe andtolerable antidiabetic therapies, particularly for obese or overweightdiabetes patients.

Further, it remains a need in the art to provide efficacious, safe andtolerable therapies for obesity patients with or without diabetes,particularly for reducing body weight and maintaining reduced bodyweight as well as for preventing rebound of weight gain followingcessation of weight loss treatment in such patients.

Within the management of the dual epidemic of type 2 diabetes andobesity (“diabesity”), it is an objective to find therapies which aresafe, tolerable and effective in the treatment or prevention of theseconditions together, particularly in achieving long term weightreduction and improving glycemic control.

Further, within the therapy of type 2 diabetes, obesity or both, it is aneed for treating the condition effectively, avoiding the complicationsinherent to the condition, and delaying disease progression.

Furthermore, it remains a need that antidiabetic treatments not onlyprevent the long-term complications often found in advanced stages ofdiabetes disease, but also are a therapeutic option in those diabetespatients who have developed complications, such as renal impairment.

Moreover, it remains a need to provide prevention or reduction of riskfor adverse effects associated with conventional antidiabetic therapies.

The enzyme DPP-4 (dipeptidyl peptidase IV) also known as CD26 is aserine protease known to lead to the cleavage of a dipeptide from theN-terminal end of a number of proteins having at their N-terminal end aprolin or alanin residue. Due to this property DPP-4 inhibitorsinterfere with the plasma level of bioactive peptides including thepeptide GLP-1 and are considered to be promising drugs for the treatmentof diabetes mellitus.

For example, DPP-4 inhibitors and their uses are disclosed in WO2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469, WO2004/041820, WO 2004/046148, WO 2005/051950, WO 2005/082906, WO2005/063750, WO 2005/085246, WO 2006/027204, WO 2006/029769,WO2007/014886; WO 2004/050658, WO 2004/111051, WO 2005/058901, WO2005/097798; WO 2006/068163, WO 2007/071738, WO 2008/017670; WO2007/128721, WO 2007/128724, WO 2007/128761, or WO 2009/121945.

Glucagon-like peptide-1 (GLP-1) is a hormon secreted fromenteroendocrine L cells of the intestine in response to food. ExogenousGLP-1 administration at pharmacological doses results in effects thatare beneficial for treating type 2 diabetes. However, native GLP-1 issubject to rapid enzymatic degradation. The action of GLP-1 is mediatedthrough the GLP-1 receptor (GLP-1R).

In the monitoring of the treatment of diabetes mellitus the HbA1c value,the product of a non-enzymatic glycation of the haemoglobin B chain, isof exceptional importance. As its formation depends essentially on theblood sugar level and the life time of the erythrocytes the HbA1c in thesense of a “blood sugar memory” reflects the average blood sugar levelof the preceding 4-12 weeks. Diabetic patients whose HbA1c level hasbeen well controlled over a long time by more intensive diabetestreatment (i.e. <6.5% of the total haemoglobin in the sample) aresignificantly better protected from diabetic microangiopathy. Theavailable treatments for diabetes can give the diabetic an averageimprovement in their HbA1c level of the order of 1.0-1.5%. Thisreduction in the HbA1C level is not sufficient in all diabetics to bringthem into the desired target range of <7.0%, preferably <6.5% and morepreferably <6% HbA1c.

Within the meaning of this invention, inadequate or insufficientglycemic control means in particular a condition wherein patients showHbA1c values above 6.5%, in particular above 7.0%, even more preferablyabove 7.5%, especially above 8%. An embodiment of patients withinadequate or insufficient glycemic control include, without beinglimited to, patients having a HbA1c value from 7.5 to 10% (or, inanother embodiment, from 7.5 to 11%). A special sub-embodiment ofinadequately controlled patients refers to patients with poor glycemiccontrol including, without being limited, patients having a HbA1c value9%.

Within glycemic control, in addition to improvement of the HbA1c level,other recommended therapeutic goals for type 2 diabetes mellituspatients are improvement of fasting plasma glucose (FPG) and ofpostprandial plasma glucose (PPG) levels to normal or as near normal aspossible. Recommended desired target ranges of preprandial (fasting)plasma glucose are 70-130 mg/dL (or 90-130 mg/dL) or <110 mg/dL, and oftwo-hour postprandial plasma glucose are <180 mg/dL or <140 mg/dL.

In one embodiment, diabetes patients within the meaning of thisinvention may include patients who have not previously been treated withan antidiabetic drug (drug-naïve patients). Thus, in an embodiment, thetherapies described herein may be used in naïve patients. In anotherembodiment, diabetes patients within the meaning of this invention mayinclude patients with advanced or late stage type 2 diabetes mellitus(including patients with failure to conventional antidiabetic therapy),such as e.g. patients with inadequate glycemic control on one, two ormore conventional oral and/or non-oral antidiabetic drugs as definedherein, such as e.g. patients with insufficient glycemic control despite(mono-) therapy with metformin, a thiazolidinedione (particularlypioglitazone), a sulphonylurea, a glinide, GLP-1 or GLP-1 analogue,insulin or insulin analogue, or an α-glucosidase inhibitor, or despitedual combination therapy with metformin/sulphonylurea,metformin/thiazolidinedione (particularly pioglitazone),metformin/insulin, pioglitazone/sulphonylurea, pioglitazone/insulin, orsulphonylurea/insulin. Thus, in an embodiment, the therapies describedherein may be used in patients experienced with therapy, e.g. withconventional oral and/or non-oral antidiabetic mono- or dual or triplecombination medication as mentioned herein.

A further embodiment of diabetic patients within the meaning of thisinvention refers to patients ineligible for metformin therapy including

-   -   patients for whom metformin therapy is contraindicated, e.g.        patients having one or more contraindications against metformin        therapy according to label, such as for example patients with at        least one contraindication selected from:        -   renal disease, renal impairment or renal dysfunction (e.g.,            as specified by product information of locally approved            metformin),        -   dehydration,        -   unstable or acute congestive heart failure,        -   acute or chronic metabolic acidosis, and        -   hereditary galactose intolerance;            and    -   patients who suffer from one or more intolerable side effects        attributed to metformin, particularly gastrointestinal side        effects associated with metformin, such as for example patients        suffering from at least one gastrointestinal side effect        selected from:        -   nausea,        -   vomiting,        -   diarrhoea,        -   intestinal gas, and        -   severe abdominal discomfort.

A further embodiment of the diabetes patients which may be amenable tothe therapies of this invention may include, without being limited,those diabetes patients for whom normal metformin therapy is notappropriate, such as e.g. those diabetes patients who need reduced dosemetformin therapy due to reduced tolerability, intolerability orcontraindication against metformin or due to (mildly) impaired/reducedrenal function (including elderly patients, such as e.g. ≧60-65 years).

A further embodiment of diabetic patients within the meaning of thisinvention refers to patients having renal disease, renal dysfunction, orinsufficiency or impairment of renal function (including mild, moderateand severe renal impairment), e.g. as suggested by elevated serumcreatinine levels (e.g. serum creatinine levels above the upper limit ofnormal for their age, e.g. ≧130-150 μmol/l, or ≧1.5 mg/dl 136 μmol/l) inmen and ≧1.4 mg/dl (≧124 μmol/l) in women) or abnormal creatinineclearance (e.g. glomerular filtration rate (GFR)≦30-60 ml/min).

In this context, for more detailed example, mild renal impairment may bee.g. suggested by a creatinine clearance of 50-80 ml/min (approximatelycorresponding to serum creatine levels of ≦1.7 mg/dL in men and ≦1.5mg/dL in women); moderate renal impairment may be e.g. suggested by acreatinine clearance of 30-50 ml/min (approximately corresponding toserum creatinine levels of >1.7 to ≦3.0 mg/dL in men and >1.5 to ≦2.5mg/dL in women); and severe renal impairment may be e.g. suggested by acreatinine clearance of <30 ml/min (approximately corresponding to serumcreatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women).Patients with end-stage renal disease require dialysis (e.g.hemodialysis or peritoneal dialysis).

For other more detailed example, patients with renal disease, renaldysfunction or renal impairment include patients with chronic renalinsufficiency or impairment, which can be stratified according toglomerular filtration rate (GFR, ml/min/1.73 m²) into 5 disease stages:stage 1 characterized by normal GFR 90 plus either persistentalbuminuria or known structural or hereditary renal disease; stage 2characterized by mild reduction of GFR (GFR 60-89) describing mild renalimpairment; stage 3 characterized by moderate reduction of GFR (GFR30-59) describing moderate renal impairment; stage 4 characterized bysevere reduction of GFR (GFR 15-30) describing severe renal impairment;and terminal stage 5 characterized by requiring dialysis or GFR<15describing established kidney failure (end-stage renal disease, ESRD).

Within the scope of the present invention it has now been found thatcertain DPP-4 inhibitors as defined herein as well as pharmaceuticalcombinations, compositions or combined uses according to this inventionof these DPP-4 inhibitors and GLP-1 receptor agonists (e.g. exogenousGLP-1 or GLP-1 analogues) as defined herein have unexpected andparticularly advantageous properties, which make them suitable for thepurpose of this invention and/or for fulfilling one or more of aboveneeds.

The present invention thus relates to a combination comprising a certainDPP-4 inhibitor (particularly BI 1356) and a GLP-1 receptor agonist(e.g. exogenous GLP-1 or a GLP-1 analogue), each as defined herein,particularly for simultaneous, separate or sequential use in thetherapies described herein.

The present invention further relates to a method for treating and/orpreventing metabolic diseases, especially type 2 diabetes mellitus,obesity and/or conditions related thereto (e.g. diabetic complications)comprising the combined (e.g. simultaneous, separate or sequential)administration of an effective amount of a GLP-1 receptor agonist (e.g.exogenous GLP-1 or a GLP-1 analogue) as defined herein and of aneffective amount of a DPP-4 inhibitor as defined herein to the patient(particularly human patient) in need thereof, such as e.g a patient asdescribed herein.

The present invention further relates to at least one of the followingmethods:

-   -   preventing, slowing the progression of, delaying or treating a        metabolic disorder or disease, such as e.g. type 1 diabetes        mellitus, type 2 diabetes mellitus, impaired glucose tolerance        (IGT), impaired fasting blood glucose (IFG), hyperglycemia,        postprandial hyperglycemia, overweight, obesity, dyslipidemia,        hyperlipidemia, hypercholesterolemia, hypertension,        atherosclerosis, endothelial dysfunction, osteoporosis, chronic        systemic inflammation, non alcoholic fatty liver disease        (NAFLD), retinopathy, neuropathy, nephropathy, polycystic        ovarian syndrome, and/or metabolic syndrome;    -   improving glycemic control and/or for reducing of fasting plasma        glucose, of postprandial plasma glucose and/or of glycosylated        hemoglobin HbA1c;    -   preventing, slowing, delaying or reversing progression from        pre-diabetes, impaired glucose tolerance (IGT), impaired fasting        blood glucose (IFG), insulin resistance and/or from metabolic        syndrome to type 2 diabetes mellitus;    -   preventing, reducing the risk of, slowing the progression of,        delaying or treating of complications of diabetes mellitus such        as micro- and macrovascular diseases, such as nephropathy,        micro- or macroalbuminuria, proteinuria, retinopathy, cataracts,        neuropathy, learning or memory impairment, neurodegenerative or        cognitive disorders, cardio- or cerebrovascular diseases, tissue        ischaemia, diabetic foot or ulcus, atherosclerosis,        hypertension, endothelial dysfunction, myocardial infarction,        acute coronary syndrome, unstable angina pectoris, stable angina        pectoris, peripheral arterial occlusive disease, cardiomyopathy,        heart failure, heart rhythm disorders, vascular restenosis,        and/or stroke;    -   reducing body weight and/or body fat and/or liver fat and/or        intra-myocellular fat or preventing an increase in body weight        and/or body fat and/or liver fat and/or intra-myocellular fat or        facilitating a reduction in body weight and/or body fat and/or        liver fat and/or intra-myocellular fat;    -   preventing, slowing, delaying or treating the degeneration of        pancreatic beta cells and/or the decline of the functionality of        pancreatic beta cells and/or for improving and/or restoring the        functionality of pancreatic beta cells and/or stimulating and/or        restoring or protecting the functionality of pancreatic insulin        secretion;    -   preventing, slowing, delaying or treating non alcoholic fatty        liver disease (NAFLD) including hepatic steatosis, non-alcoholic        steatohepatitis (NASH) and/or liver fibrosis (such as e.g.        preventing, slowing the progression, delaying, attenuating,        treating or reversing hepatic steatosis, (hepatic) inflammation        and/or an abnormal accumulation of liver fat);    -   preventing, slowing the progression of, delaying or treating        type 2 diabetes with failure to conventional antidiabetic mono-        or combination therapy;    -   achieving a reduction in the dose of conventional antidiabetic        medication required for adequate therapeutic effect;    -   reducing the risk for adverse effects associated with        conventional antidiabetic medication; and/or    -   maintaining and/or improving the insulin sensitivity and/or for        treating or preventing hyperinsulinemia and/or insulin        resistance;        in a patient in need thereof (such as e.g a patient as described        herein), said method comprising combined (e.g. simultaneous,        separate or sequential) administration of a DPP-4 inhibitor as        defined herein and a GLP-1 receptor agonist as defined herein.

In addition, the present invention relates to the combination accordingto this invention comprising a DPP-4 inhibitor as defined herein and aGLP-1 receptor agonist as defined herein for use in treating and/orpreventing (including slowing the progession or delaying the onset) ofmetabolic diseases as defined herein, particularly diabetes (especiallytype 2 diabetes and obesity, or conditions related thereto, includingdiabetic complications), optionally in combination with one or moreother therapeutic agents as described herein.

In addition, the present invention relates to the use of a combinationaccording to this invention comprising a DPP-4 inhibitor as definedherein and a GLP-1 receptor agonist as defined herein for themanufacture of a medicament for use in a therapeutic method as describedhereinbefore or hereinafter.

In addition, the present invention relates to a combination according tothis invention comprising a DPP-4 inhibitor as defined herein and aGLP-1 receptor agonist as defined herein for use in a therapeutic methodas described hereinbefore or hereinafter.

In addition, the present invention relates to a method of treatingand/or preventing (including slowing the progession or delaying theonset) of a metabolic disease, particularly diabetes (especially type 2diabetes or conditions related thereto, including diabeticcomplications) comprising administering to the patient in need thereof(such as e.g a patient as described herein) a combination according tothis invention comprising a DPP-4 inhibitor as defined herein and aGLP-1 receptor agonist as defined herein.

In addition, the present invention relates to the use of a DPP-4inhibitor as defined herein for the manufacture of a medicament for usein combination with a GLP-1 receptor agonist as defined herein fortreating and/or preventing (including slowing the progession or delayingthe onset) of metabolic diseases, particularly diabetes (especially type2 diabetes and conditions related thereto, including diabeticcomplications).

In addition, the present invention relates to the use of a GLP-1receptor agonist as defined herein for the manufacture of a medicamentfor use in combination with a DPP-4 inhibitor as defined herein fortreating and/or preventing (including slowing the progession or delayingthe onset) of metabolic diseases, particularly diabetes (especially type2 diabetes and conditions related thereto, including diabeticcomplications).

In addition, the present invention relates a DPP-4 inhibitor as definedherein for use in a combination treatment according to the invention ina patient in need thereof (such as e.g a patient as described herein).

In addition, the present invention relates a GLP-1 receptor agonist asdefined herein for use in a combination treatment according to theinvention in a patient in need thereof (such as e.g a patient asdescribed herein).

In addition, the present invention relates a DPP-4 inhibitor as definedherein, optionally in combination with one or more other activesubstances (such as e.g. metformin or pioglitazone), for use in acombination treatment according to the invention in a patient in needthereof.

In addition, the invention relates to a DPP-4 inhibitor as definedherein for use in a method as described hereinbefore or hereinafter,said method comprising administering the DPP-4 inhibitor, optionally incombination with one or more other active substances (e.g. which mayselected from those mentioned herein, such as e.g. metformin orpioglitazone), to the patient.

In an embodiment, the present invention relates to a method for reducingand maintaining body weight and/or body fat in a patient in need thereof(particularly type 2 diabetes patient being obese or overweight)comprising administering a combination comprising a GLP-1 receptoragonist (e.g. GLP-1 or GLP-1 analogue as defined herein) and a DPP-4inhibitor as defined herein to the patient.

In an embodiment, the present invention relates to a method for reducingand maintaining body weight and/or body fat in a patient in need thereof(particularly type 2 diabetes patient being obese or overweight)comprising i) inducing body weight and/or body fat loss (e.g. by diet,exercise and/or treatment with an anti-obesity or body weight reducingagent as described herein, particularly by administering an effectiveamount of the GLP-1 receptor agonist to the patient) and ii.)administering an effective amount of a certain DPP-4 inhibitor to thepatient, wherein, optionally, said DPP-4 inhibitor may be used asreplacement of the weight and/or fat loss treatment i) or as add-on orinitial combination therapy with the weight and/or fat loss treatmenti).

In a particular embodiment, the present invention relates to a DPP-4inhibitor as defined herein, optionally in combination with one or moreother therapeutic agents, for use in a method of preventing body weightand/or body fat gain or controlling, stabilizing or maintaining areduced body weight and/or body fat after initial weight reducingtreatment (such as e.g. diet, exercise and/or treatment with ananti-obesity or body weight reducing agent as described herein),particularly after discontinuation of initial treatment with a GLP-1receptor agonist (e.g. GLP-1 or GLP-1 analogue as defined herein), in apatient in need thereof.

In a particular embodiment, the present invention relates to a methodfor reducing and maintaining body weight and/or body fat in a patient inneed thereof (particularly type 2 diabetes patient being obese oroverweight) comprising the combined (e.g. separate, simultaneous orsequential) administration of a GLP-1 receptor agonist (e.g. GLP-1 orGLP-1 analogue as defined herein) and a DPP-4 inhibitor as definedherein; preferably said method comprising the sequential administrationof the GLP-1 receptor agonist followed by the DPP-4 inhibitor.

In a particular embodiment, the present invention relates to a methodfor reducing and maintaining body weight and/or body fat in a patient inneed thereof (particularly type 2 diabetes patient being obese oroverweight), said method comprising i) inducing body weight and/or bodyfat loss (e.g. by administering an effective amount of a GLP-1 receptoragonist (e.g. GLP-1 or GLP-1 analogue as defined herein) to the patient)and ii.) administering an effective amount of a DPP-4 inhibitor asdefined herein to the patient for maintaining the body weight and/orbody fat loss.

In a particular embodiment, the present invention relates to a methodfor reducing and maintaining body weight and/or body fat in a patient inneed thereof (particularly type 2 diabetes patient being obese oroverweight), said method comprising i) inducing initial body weightand/or body fat loss (e.g. by administering an effective amount of aGLP-1 receptor agonist (e.g. GLP-1 or GLP-1 analogue as defined herein)to the patient) and, subsequently, ii.) administering an effectiveamount of a DPP-4 inhibitor as defined herein to the patient, preferablythereby replacing the GLP-1 receptor agonist.

In a particular embodiment, the present invention relates to a DPP-4inhibitor as defined herein for use in preventing of body weight and/orbody fat gain or controlling, stabilizing or maintaining a reduced bodyweight and/or body fat after discontinuation of a weight reducingtreatment (such as e.g. diet, exercise and/or treatment with ananti-obesity or body weight reducing agent as described herein),particularly after discontinuation of treatment with a GLP-1 receptoragonist (e.g. GLP-1 or GLP-1 analogue as defined herein), in a patientin need thereof (such as e.g a patient as described herein).

In a particular embodiment, the present invention relates to the use ofa DPP-4 inhibitor as defined herein for the manufacture of a medicamentfor use in preventing of body weight and/or body fat gain orcontrolling, stabilizing or maintaining a reduced body weight and/orbody fat after initial weight reducing treatment (such as e.g. usingdiet, exercise and/or treatment with an anti-obesity or body weightreducing agent as described herein), particularly after initialtreatment with a GLP-1 receptor agonist (e.g. GLP-1 or GLP-1 analogue asdefined herein).

In a particular embodiment, the present invention relates to a method ofpreventing body weight gain and/or body fat gain or controlling,stabilizing or maintaining a reduced body weight and/or body fat afterinitial weight reducing treatment (such as e.g. using diet, exerciseand/or treatment with an anti-obesity or body weight reducing agent asdescribed herein), particularly after initial treatment with a GLP-1receptor agonist (e.g. GLP-1 or GLP-1 analogue as defined herein), saidmethod comprising administering an effective amount of a DPP-4 inhibitoras defined herein to the patient in need thereof.

In a particular embodiment, the present invention relates to a certainDPP-4 inhibitor for use in a method of reducing and maintaining bodyweight and/or body fat, or of attenuating, preventing or treatingrebound of body weight gain and/or body fat gain followingdiscontinuation of body weight loss treatment (particularly followingdiscontinuation of treatment with a GLP-1 receptor agonist),particularly in obesity patients with or without diabetes, said methodcomprising administering a certain DPP-4 inhibitor (particularlylinagliptin) subsequent to the body weight loss treatment (particularlysubsequent to the treatment with the GLP-1 receptor agonist), optionallyin combination with one or more other therapeutic agents.

In alternative to the use of a GLP-1 receptor agonist (e.g. GLP-1 orGLP-1 analogue as defined herein), the initial weight and/or fat lossmay also be induced by using diet, exercise and/or treatment with ananti-obesity or body weight reducing agent, such as e.g. one or moreagents selected from sibutramine, a lipase inhibitor such astetrahydrolipstatin (orlistat) or alizyme (cetilistat), a cannabinoidreceptor 1 antagonist (e.g. rimonabant), a MC4 receptor agonist, a NPYreceptor agonist such as e.g. a NPY2 antagonist (e.g. velneperit), a5HT2c receptor agonist (e.g. lorcaserin), a Ghrelin antagonist, Pyy3-36, leptin, a DGAT-1 inhibitor, a noradrenaline-dopamine-5HT reuptakeinhibitor (e.g. tesofensine), bupropion/naltrexone,bupropion/zonisamide, topiramate/phentermine andpramlintide/metreleptin; or a MCH antagonist, a CCK inhibitor, a FASinhibitor, an ACC inhibitor, a SCD inhibitor, a beta3adrenoreceptoragonist, a MTP inhibitor (e.g. lomitapide) or amylin or an amylinanalogue (e.g. davalintide or pramlintide).

Within an embodiment of the combination therapy of this invention (e.g.for treating type 2 diabetes, obesity or both, or for reducing andmaintaining body weight), the GLP-1 receptor agonist may be used forinducing (initial) body weight loss, and/or the DPP-4 inhibitor may beused for maintaining body weight loss.

Another embodiment of the combination therapy of this invention (e.g.for treating type 2 diabetes, obesity or both, or for reducing andmaintaining body weight and/or body fat), refers to a method comprising

-   i) administering an effective amount of a GLP-1 receptor agonist to    the patient, particularly for inducing body weight and/or body fat    loss in the patient,-   ii) withdrawing the GLP-1 receptor agonist from the patient,    particularly after the body weight and/or body fat is reduced in the    patient, and-   iii) administering an effective amount of a DPP-4 inhibitor to the    patient, particularly for delaying body weight and/or body fat gain    and/or maintaining reduction in body weight and/or in body fat in    the patient.

Another embodiment of the combination therapy of this invention refersto the use of a certain DPP-4 inhibitor (particularly linagliptin)subsequent to body weight loss, particularly subsequent to a GLP-1receptor agonist, optionally in combination with one or more othertherapeutic agents.

Other aspects of the present invention become apparent to the skilledperson from the foregoing and following remarks (including the examplesand claims).

The aspects of the present invention, in particular the pharmaceuticalcompounds, compositions, combinations, methods and uses, refer to DPP-4inhibitors and/or GLP-1 receptor agonists as defined hereinbefore andhereinafter.

A DPP-4 inhibitor within the meaning of the present invention includes,without being limited to, any of those DPP-4 inhibitors mentionedhereinabove and hereinbelow, preferably orally active DPP-4 inhibitors.

An embodiment of this invention refers to a DPP-4 inhibitor for use inthe treatment and/or prevention of metabolic diseases (particularly type2 diabetes mellitus) in type 2 diabetes patients, wherein said patientsfurther suffering from renal disease, renal dysfunction or renalimpairment, particularly characterized in that said DPP-4 inhibitor isadministered to said patients in the same dose levels as to patientswith normal renal function, thus e.g. said DPP-4 inhibitor does notrequire downward dosing adjustment for impaired renal function.

For example, a DPP-4 inhibitor according to this invention (especiallyone which may be suited for patients with impaired renal function) maybe such an oral DPP-4 inhibitor, which and whose active metabolites havepreferably a relatively wide (e.g. about >100 fold) therapeutic windowand/or, especially, that are primarily eliminated via hepatic metabolismor biliary excretion.

In more detailed example, a DPP-4 inhibitor according to this invention(especially one which may be suited for patients with impaired renalfunction) may be such an orally administered DPP-4 inhibitor, which hasa relatively wide (e.g. >100 fold) therapeutic window and/or whichfulfils one or more of the following pharmacokinetic properties(preferably at its therapeutic oral dose levels):

-   -   The DPP-4 inhibitor is substantially or mainly excreted via the        liver (e.g. >80% or even>90% of the administered oral dose),        and/or for which renal excretion represents no substantial or        only a minor elimination pathway (e.g. <10%, preferably <7%, of        the administered oral dose measured, for example, by following        elimination of a radiolabelled carbon (¹⁴C) substance oral        dose);    -   The DPP-4 inhibitor is excreted mainly unchanged as parent drug        (e.g. with a mean of >70%, or >80%, or, preferably, 90% of        excreted radioactivity in urine and faeces after oral dosing of        radiolabelled carbon (¹⁴C) substance), and/or which is        eliminated to a non-substantial or only to a minor extent via        metabolism (e.g. <30%, or <20%, or, preferably, 10%);    -   The (main) metabolite(s) of the DPP-4 inhibitor is/are        pharmacologically inactive. Such as e.g. the main metabolite        does not bind to the target enzyme DPP-4 and, optionally, it is        rapidly eliminated compared to the parent compound (e.g. with a        terminal half-life of the metabolite of ≦20 h, or, preferably,        ≦about 16 h, such as e.g. 15.9 h).

In one embodiment, the (main) metabolite in plasma (which may bepharmacologically inactive) of a DPP-4 inhibitor having a3-amino-piperidin-1-yl substituent is such a derivative where the aminogroup of the 3-amino-piperidin-1-yl moiety is replaced by a hydroxylgroup to form the 3-hydroxy-piperidin-1-yl moiety (e.g. the3-(S)-hydroxy-piperidin-1-yl moiety, which is formed by inversion of theconfiguration of the chiral center).

Further properties of a DPP-4 inhibitor according to this invention maybe one or more of the following: Rapid attainment of steady state (e.g.reaching steady state plasma levels (>90% of the steady state plasmaconcentration) between second and fifth day of treatment withtherapeutic oral dose levels), little accumulation (e.g. with a meanaccumulation ratio R_(A,AUC)≦1.4 with therapeutic oral dose levels),and/or preserving a long-lasting effect on DPP-4 inhibition, preferablywhen used once-daily (e.g. with almost complete (>90%) DPP-4 inhibitionat therapeutic oral dose levels, >80% inhibition over a 24 h intervalafter once-daily intake of therapeutic oral drug dose), significantdecrease in 2 h postprandial blood glucose excursions by ≧80% (alreadyon first day of therapy) at therapeutic dose levels, and cumulativeamount of unchanged parent compound excreted in urine on first day beingbelow 1% of the administered dose and increasing to not more than about3-6% in steady state.

Thus, for example, a DPP-4 inhibitor according to this invention may becharacterized in that said DPP-4 inhibitor is excreted to anon-substantial or only to a minor extent (e.g. <10%, preferably <7% ofadministered oral dose) via the kidney (measured, for example, byfollowing elimination of a radiolabelled carbon (¹⁴C) substance oraldose).

Further, a DPP-4 inhibitor according to this invention may becharacterized in that said DPP-4 inhibitor is excreted substantially ormainly via the liver or faeces (measured, for example, by followingelimination of a radiolabelled carbon (¹⁴C) substance oral dose).

Further, a DPP-4 inhibitor according to this invention may becharacterized in that said DPP-4 inhibitor is excreted mainly unchangedas parent drug (e.g. with a mean of >70%, or >80%, or, preferably, 90%of excreted radioactivity in urine and faeces after oral dosing ofradiolabelled carbon (¹⁴C) substance),

said DPP-4 inhibitor is eliminated to a non-substantial or only to aminor extent via metabolism, and/or

the main metabolite of said DPP-4 inhibitor is pharmacologicallyinactive or has a relatively wide therapeutic window.

Further, a DPP-4 inhibitor according to this invention may becharacterized in that said DPP-4 inhibitor does not significantly impairglomerular and/or tubular function of a type 2 diabetes patient withchronic renal insufficiency (e.g. mild, moderate or severe renalimpairment or end stage renal disease), and/or

said DPP-4 inhibitor does not require to be dose-adjusted in a type 2diabetes patient with impaired renal function (e.g. mild, moderate orsevere renal impairment or end stage renal disease).

Further, a DPP-4 inhibitor according to this invention may becharacterized in that said DPP-4 inhibitor provides its minimallyeffective dose at that dose that results in >50% inhibition of DPP-4activity at trough (24 h after last dose) in >80% of patients, and/orsaid DPP-4 inhibitor provides its fully therapeutic dose at that dosethat results in >80% inhibition of DPP-4 activity at trough (24 h afterlast dose) in >80% of patients.

In a first embodiment (embodiment A), a DPP-4 inhibitor in the contextof the present invention is any DPP-4 inhibitor of

formula (I)

or formula (II)

or formula (III)

or formula (IV)

wherein R1 denotes ([1,5]naphthyridin-2-yl)methyl,(quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl,(4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl,(3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl,(4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyland R2 denotes 3-(R)-amino-piperidin-1-yl,(2-amino-2-methyl-propyl)methylaminoor (2-(S)-amino-propyl)-methylamino, or its pharmaceutically acceptablesalt.

In a second embodiment (embodiment B), a DPP-4 inhibitor in the contextof the present invention is a DPP-4 inhibitor selected from the groupconsisting of sitagliptin, vildagliptin, saxagliptin, alogliptin,gemigliptin,

-   (2S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile,-   (2S)-1-{[1,1,-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile,-   (S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one,-   (3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone,-   (1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one,-   (2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-fluoropyrrolidine-2-carbonitrile,-   (R)-2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile,-   5-{(S)-2-[2-((S)-2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic    acid bis-dimethylamide,-   3-{(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine,-   [(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic    acid,-   (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile,-   2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile,-   6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione,    and-   (S)-2-methylpyrazolo[1,5-a]primidine-6-carboxylic acid    {2-[(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methylpropyl}amide,    or its pharmaceutically acceptable salt.

Regarding the first embodiment (embodiment A), preferred DPP-4inhibitors are any or all of the following compounds and theirpharmaceutically acceptable salts:

-   -   1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine        (compare WO 2004/018468, example 2(142)):

-   -   1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2004/018468, example 2(252)):

-   -   1-[(Quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2004/018468, example 2(80)):

-   -   2-((R)-3-Amino-piperidin-1-yl)-3-(but-2-yinyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one        (compare WO 2004/050658, example 136):

-   -   1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyln-1-yl)-8-[(2-amino-2-methyl-propyl)-methylamino]-xanthine        (compare WO 2006/029769, example 2(1)):

-   -   1-[(3-Cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2005/085246, example 1(30)):

-   -   1-(2-Cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2005/085246, example 1(39)):

-   -   1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino]-xanthine        (compare WO 2006/029769, example 2(4)):

-   -   1-[(3-Cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2005/085246, example 1(52)):

-   -   1-[(4-Methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(R)-3-amino-piperidin-1-ylyxanthine        (compare WO 2005/085246, example 1(81)):

-   -   1-[(4,6-Dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2005/085246, example 1(82)):

-   -   1-[(Quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2005/085246, example 1(83)):

These DPP-4 inhibitors are distinguished from structurally comparableDPP-4 inhibitors, as they combine exceptional potency and a long-lastingeffect with favourable pharmacological properties, receptor selectivityand a favourable side-effect profile or bring about unexpectedtherapeutic advantages or improvements when combined with otherpharmaceutical active substances. Their preparation is disclosed in thepublications mentioned.

A more preferred DPP-4 inhibitor among the abovementioned DPP-4inhibitors of embodiment A of this invention is1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,particularly the free base thereof (which is also known as linagliptinor BI 1356).

As further DPP-4 inhibitors the following compounds can be mentioned:

-   -   Sitagliptin (MK-0431) having the structural formula A below is        (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one,        also named        (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine,

In one embodiment, sitagliptin is in the form of its dihydrogenphosphatesalt, i.e. sitagliptin phosphate. In a further embodiment, sitagliptinphosphate is in the form of a crystalline anhydrate or monohydrate. Aclass of this embodiment refers to sitagliptin phosphate monohydrate.Sitagliptin free base and pharmaceutically acceptable salts thereof aredisclosed in U.S. Pat. No. 6,699,871 and in Example 7 of WO 03/004498.Crystalline sitagliptin phosphate monohydrate is disclosed in WO2005/003135 and in WO 2007/050485.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

A tablet formulation for sitagliptin is commercially available under thetrade name Januvia®. A tablet formulation for sitagliptin/metformincombination is commercially available under the trade name Janumet®.

-   -   Vildagliptin (LAF-237) having the structural formula B below is        (2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}pyrrolidine-2-carbonitrile,        also named        (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine,

Vildagliptin is specifically disclosed in U.S. Pat. No. 6,166,063 and inExample 1 of WO 00/34241. Specific salts of vildagliptin are disclosedin WO 2007/019255. A crystalline form of vildagliptin as well as avildagliptin tablet formulation are disclosed in WO 2006/078593.Vildagliptin can be formulated as described in WO 00/34241 or in WO2005/067976. A modified release vildagliptin formulation is described inWO 2006/135723.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

A tablet formulation for vildagliptin is expected to be commerciallyavailable under the trade name Galvus®. A tablet formulation forvildagliptin/metformin combination is commercially available under thetrade name Eucreas®.

-   -   Saxagliptin (BMS-477118) having the structural formula C below        is        (1S,3S,5S)-2-{(25)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl}-2-azabicyclo[3.1.0]hexane-3-carbonitrile,        also named        (S)-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile,

Saxagliptin is specifically disclosed in U.S. Pat. No. 6,395,767 and inExample 60 of WO 01/68603.

In one embodiment, saxagliptin is in the form of its HCl salt or itsmono-benzoate salt as disclosed in WO 2004/052850. In a furtherembodiment, saxagliptin is in the form of the free base. In a yetfurther embodiment, saxagliptin is in the form of the monohydrate of thefree base as disclosed in WO 2004/052850. Crystalline forms of the HClsalt and of the free base of saxagliptin are disclosed in WO2008/131149. A process for preparing saxagliptin is also disclosed in WO2005/106011 and WO 2005/115982. Saxagliptin can be formulated in atablet as described in WO 2005/117841.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

-   -   Alogliptin (SYR-322) having the structural formula E below is        2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrmidin-1-yl}methyl)benzonitrile

Alogliptin is specifically disclosed in US 2005/261271, EP 1586571 andin WO 2005/095381. In one embodiment, alogliptin is in the form of itsbenzoate salt, its hydrochloride salt or its tosylate salt each asdisclosed in WO 2007/035629. A class of this embodiment refers toalogliptin benzoate. Polymorphs of alogliptin benzoate are disclosed inWO 2007/035372. A process for preparing alogliptin is disclosed in WO2007/112368 and, specifically, in WO 2007/035629. Alogliptin (namely itsbenzoate salt) can be formulated in a tablet and administered asdescribed in WO 2007/033266. A solid preparation ofalogliptin/pioglitazone and its preparation and use is described in WO2008/093882. A solid preparation of alogliptin/metformin and itspreparation and use is described in WO 2009/011451.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

-   -   (2S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile        or a pharmaceutically acceptable salt thereof, preferably the        mesylate, or    -   (2S)-1-{[1,1,-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile        or a pharmaceutically acceptable salt thereof:

These compounds and methods for their preparation are disclosed in WO03/037327. The mesylate salt of the former compound as well ascrystalline polymorphs thereof are disclosed in WO 2006/100181. Thefumarate salt of the latter compound as well as crystalline polymorphsthereof are disclosed in WO 2007/071576. These compounds can beformulated in a pharmaceutical composition as described in WO2007/017423. For details, e.g. on a process to manufacture, to formulateor to use these compounds or salts thereof, reference is thus made tothese documents.

-   -   (S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one        (also named carmegliptin) or a pharmaceutically acceptable salt        thereof:

This compound and methods for its preparation are disclosed in WO2005/000848. A process for preparing this compound (specifically itsdihydrochloride salt) is also disclosed in WO 2008/031749, WO2008/031750 and WO 2008/055814. This compound can be formulated in apharmaceutical composition as described in WO 2007/017423.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

-   -   (3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone        (also named gosogliptin) or a pharmaceutically acceptable salt        thereof:

This compound and methods for its preparation are disclosed in WO2005/116014 and U.S. Pat. No. 7,291,618.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

-   -   (1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one        or a pharmaceutically acceptable salt thereof:

This compound and methods for its preparation are disclosed in WO2007/148185 and US 20070299076. For details, e.g. on a process tomanufacture, to formulate or to use this compound or a salt thereof,reference is thus made to these documents.

-   -   (2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-fluoropyrrolidine-2-carbonitrile        (alos named melogliptin) or a pharmaceutically acceptable salt        thereof:

This compound and methods for its preparation are disclosed in WO2006/040625 and WO 2008/001195. Specifically claimed salts include themethanesulfonate and p-toluenesulfonate. For details, e.g. on a processto manufacture, to formulate or to use this compound or a salt thereof,reference is thus made to these documents.

-   -   (R)-2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile        or a pharmaceutically acceptable salt thereof:

This compound and methods for its preparation and use are disclosed inWO 2005/095381, US 2007060530, WO 2007/033350, WO 2007/035629, WO2007/074884, WO 2007/112368, WO 2008/033851, WO 2008/114800 and WO2008/114807. Specifically claimed salts include the succinate (WO2008/067465), benzoate, benzenesulfonate, p-toluenesulfonate,(R)-mandelate and hydrochloride. For details, e.g. on a process tomanufacture, to formulate or to use this compound or a salt thereof,reference is thus made to these documents.

-   -   5-{(S)-2-[2-((S)-2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic        acid bis-dimethylamide or a pharmaceutically acceptable salt        thereof:

This compound and methods for its preparation are disclosed in WO2006/116157 and US 2006/270701. For details, e.g. on a process tomanufacture, to formulate or to use this compound or a salt thereof,reference is thus made to these documents.

-   -   3-{(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine        (also named teneligliptin) or a pharmaceutically acceptable salt        thereof:

This compound and methods for its preparation are disclosed in WO02/14271. Specific salts are disclosed in WO 2006/088129 and WO2006/118127 (including hydrochloride, hydrobromide, inter alia).Combination therapy using this compound is described in WO 2006/129785.For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

-   -   [(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic        acid (also named dutogliptin) or a pharmaceutically acceptable        salt thereof:

This compound and methods for its preparation are disclosed in WO2005/047297, WO 2008/109681 and WO 2009/009751. Specific salts aredisclosed in WO 2008/027273 (including citrate, tartrate). A formulationof this compound is described in WO 2008/144730. A formulation ofdutogliptin (as its tartrate salt) with metformin is described in WO2009/091663. For details, e.g. on a process to manufacture, to formulateor to use this compound or a salt thereof, reference is thus made tothese documents.

-   -   (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile        (also named bisegliptin) or a pharmaceutically acceptable salt        thereof:

This compound and methods for its preparation are disclosed in WO2005/075421, US 2008/146818 and WO 2008/114857. For details, e.g. on aprocess to manufacture, to formulate or to use this compound or a saltthereof, reference is thus made to these documents.

-   -   2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile        or a pharmaceutically acceptable salt thereof, or        6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione        or a pharmaceutically acceptable salt thereof:

These compounds and methods for their preparation are disclosed in WO2009/084497 and WO 2006/068163, respectively. Combination therapy usingthe latter of these two compounds is described in WO 2009/128360. Fordetails, e.g. on a process to manufacture, to formulate or to use thesecompounds or salts thereof, reference is thus made to these documents.

-   -   (S)-2-methylpyrazolo[1,5-a]primidine-6-carboxylic acid        {2-[(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methylpropyl}amide        (also named anagliptin) or a pharmaceutically acceptable salt:

This compound and methods for its preparation are disclosed in WO2004/067509. Combination therapy using this compound is described in WO2009/139362. For details, e.g. on a process to manufacture, to formulateor to use this compound or a salt thereof, reference is thus made tothese documents.

Preferably the DPP-4 inhibitor of this invention is selected from thegroup (group G1) consisting of linagliptin, sitagliptin, vildagliptin,alogliptin, saxagliptin, teneligliptin and dutogliptin, or apharmaceutically acceptable salt of one of the hereinmentioned DPP-4inhibitors, or a prodrug thereof.

In another embodiment, the DPP-4 inhibitor of this invention is selectedfrom the group (group H1) consisting of linagliptin, sitagliptin,vildagliptin, alogliptin, saxagliptin, teneligliptin, anagliptin,gemigliptin and dutogliptin, or a pharmaceutically acceptable salt ofone of the hereinmentioned DPP-4 inhibitors, or a prodrug thereof.

A particularly preferred DPP-4 inhibitor within the present invention islinagliptin. The term “linagliptin” as employed herein refers tolinagliptin or a pharmaceutically acceptable salt thereof, includinghydrates and solvates thereof, and crystalline forms thereof, preferablylinagliptin refers to1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine.Crystalline forms are described in WO 2007/128721. Methods for themanufacture of linagliptin are described in the patent applications WO2004/018468 and WO 2006/048427 for example. Linagliptin is distinguishedfrom structurally comparable DPP-4 inhibitors, as it combinesexceptional potency and a long-lasting effect with favourablepharmacological properties, receptor selectivity and a favourableside-effect profile or bring about unexpected therapeutic advantages orimprovements in mono- or dual or triple combination therapy.

For avoidance of any doubt, the disclosure of each of the foregoing andfollowing documents cited above in connection with the specified DPP-4inhibitors is specifically incorporated herein by reference in itsentirety.

GLP-1 receptor agonists include, without being limited, exogenous GLP-1(natural or synthetic), GLP-1 analogues (including longer actinganalogues which are resistant to or have reduced susceptibility toenzymatic degradation by DPP-4 and NEP 24.11) and other substances(whether peptidic or non-peptidic, e.g. small molecules) which promotesignalling through the GLP-1 receptor.

Examples of GLP-1 analogues may include (group G2): exenatide (syntheticexendin-4, e.g. formulated as Byetta); exenatide LAR (long actingrelease formulation of exenatide, e.g. formulated as Bydureon);liraglutide (e.g. formulated as Victoza); taspoglutide; semaglutide;albiglutide (e.g. formulated as Syncria); lixisenatide; dulaglutide; andthe di-PEGylated GLP-1 compound comprising the amino acid sequence ofthe pegylated compound of Formula I (SEQ ID NO:1) according to WO2006/124529 (the disclosure of which is incorporated herein), whereinXaa₈ is Val, Xaa₂₂ is Glu, Xaa₃₃ is Ile, and Xaa₄₆ is Cys-NH₂, andwherein one PEG molecule is covalently attached to Cys₄₅ and one PEGmolecule is covelently attached to Cys₄₆-NH₂, wherein each of the PEGmolecules used for PEGylation reaction is a 20,000 dalton linear methoxyPEG maleimide (preferably the GLP-1derivative consists of the amino acidsequence of Val⁸-Glu²²-Ile³³-Cys-NH₂ ⁴⁶-GLP-1 (SEQ ID NO: 1) (cf. SEQ IDNO:21 of WO 2009/020802, the disclosure of which is incorporatedherein).

Preferred examples of GLP-1 receptor agonists (GLP-1 analogues) of thisinvention are exenatide, exenatide LAR, liraglutide, taspoglutide,semaglutide, albiglutide, lixisenatide and dulaglutide.

GLP-1 analogues have typically significant sequence identity to GLP-1(e.g. greater than 50%, 75%, 90% or 95%) and may be derivatised, e.g. byconjunction to other proteins (e.g. albumin or IgG-Fc fusion protein) orthrough chemical modification.

Unless otherwise noted, according to this invention it is to beunderstood that the definitions of the active agents (including theDPP-4 inhibitors and GLP-1 receptor agonists) mentioned hereinabove andhereinbelow may also contemplate their pharmaceutically acceptablesalts, and prodrugs, hydrates, solvates and polymorphic forms thereof.Particularly the terms of the therapeutic agents given herein refer tothe respective active drugs. With respect to salts, hydrates andpolymorphic forms thereof, particular reference is made to those whichare referred to herein.

In an embodiment the combinations, compositions, methods and usesaccording to this invention relate to combinations wherein the DPP-4inhibitor and the GLP-1 receptor agonist are preferably selectedaccording to the entries in the Table 1:

TABLE 1 DPP-4 Inhibitor GLP-1 receptor agonist selected from embodimentB selected from group G2 selected from embodiment B exenatide selectedfrom embodiment B exenatide LAR selected from embodiment B liraglutideselected from embodiment B taspoglutide selected from embodiment Bsemaglutide selected from embodiment B albiglutide selected fromembodiment B lixisenatide selected from embodiment B dulaglutideselected from group G1 selected from group G2 selected from group G1exenatide selected from group G1 exenatide LAR selected from group G1liraglutide selected from group G1 taspoglutide selected from group G1semaglutide selected from group G1 albiglutide selected from group G1lixisenatide selected from group G1 dulaglutide linagliptin exenatidelinagliptin exenatide LAR linagliptin liraglutide linagliptintaspoglutide linagliptin semaglutide linagliptin albiglutide linagliptinlixisenatide linagliptin dulaglutide linagliptin selected from group G2

In a particular embodiment (embodiment E) the combinations,compositions, methods and uses according to this invention relate tocombinations wherein the DPP-4 inhibitor is linagliptin. According tothis particular embodiment (embodiment E) the GLP-1 receptor agonist ispreferably selected according to the entries E1 to E8 in the Table 2:

TABLE 2 Embodiment GLP-1 receptor agonist E1 exenatide E2 exenatide LARE3 liraglutide E4 taspoglutide E5 semaglutide E6 albiglutide E7lixisenatide E8 dulaglutide

Within this invention it is to be understood that the combinations,compositions or combined uses according to this invention may envisagethe simultaneous, sequential or separate administration of the activecomponents or ingredients.

In this context, “combination” or “combined” within the meaning of thisinvention may include, without being limited, fixed and non-fixed (e.g.free) forms (including kits) and uses, such as e.g. the simultaneous,sequential or separate use of the components or ingredients.

The present invention also provides a kit-of-parts or combinationtherapeutic product comprising

-   a) a pharmaceutical composition comprising a DPP-4 inhibitor as    defined herein, optionally together with one or more    pharmaceutically acceptable carriers and/or diluents, and-   b) a pharmaceutical composition comprising a GLP-1 receptor agonist    as defined herein.

The present invention also provides a kit comprising

-   a) a DPP-4 inhibitor as defined herein, and-   b) a GLP-1 receptor agonist as defined herein,    and, optionally, instructions directing use of the DPP-4 inhibitor    and the GLP-1 receptor agonist in combination (e.g. simultaneously,    separately, sequentially or chronologically staggered), e.g. for a    purpose of this invention, such as e.g. for the treatment of type 2    diabetes, obesity and/or overweight, and/or for reducing and    maintaining body weight in a (human) patient.

The combined administration of this invention may take place byadministering the active components or ingredients together, such ase.g. by administering them simultaneously in one single or in twoseparate formulations or dosage forms. Alternatively, the administrationmay take place by administering the active components or ingredientssequentially, such as e.g. successively in two separate formulations ordosage forms.

For the combination therapy of this invention the active components oringredients may be administered separately (which implies that they areformulated separately) or formulated altogether (which implies that theyare formulated in the same preparation or in the same dosage form).Hence, the administration of one element of the combination of thepresent invention may be prior to, concurrent to, or subsequent to theadministration of the other element of the combination. Preferably, forthe combination therapy according to this invention the DPP-4 inhibitorand the GLP-1 receptor agonist are administered in differentformulations.

Unless otherwise noted, combination therapy may refer to first line,second line or third line therapy, or initial or add-on combinationtherapy or replacement therapy.

With respect to embodiment A, the methods of synthesis for the DPP-4inhibitors according to embodiment A of this invention are known to theskilled person. Advantageously, the DPP-4 inhibitors according toembodiment A of this invention can be prepared using synthetic methodsas described in the literature. Thus, for example, purine derivatives offormula (I) can be obtained as described in WO 2002/068420, WO2004/018468, WO 2005/085246, WO 2006/029769 or WO 2006/048427, thedisclosures of which are incorporated herein. Purine derivatives offormula (II) can be obtained as described, for example, in WO2004/050658 or WO 2005/110999, the disclosures of which are incorporatedherein. Purine derivatives of formula (III) and (IV) can be obtained asdescribed, for example, in WO 2006/068163, WO 2007/071738 or WO2008/017670, the disclosures of which are incorporated herein. Thepreparation of those DPP-4 inhibitors, which are specifically mentionedhereinabove, is disclosed in the publications mentioned in connectiontherewith. Polymorphous crystal modifications and formulations ofparticular DPP-4 inhibitors are disclosed in WO 2007/128721 and WO2007/128724, respectively, the disclosures of which are incorporatedherein in their entireties. Formulations of particular DPP-4 inhibitorswith metformin or other combination partners are described in WO2009/121945, the disclosure of which is incorporated herein in itsentirety.

Typical dosage strengths of the dual fixed combination (tablet) oflinagliptin/metformin IR (immediate release) are 2.5/500 mg, 2.5/850 mgand 2.5/1000 mg, which may be administered 1-3 times a day, particularlytwice a day.

Typical dosage strengths of the dual fixed combination (tablet) oflinagliptin/metformin XR (extended release) are 5/500 mg, 5/1000 mg and5/1500 mg, or 2.5/500 mg, 2.5/750 mg and 2.5/1000 mg (each two tablets),which may be administered 1-2 times a day, particularly once a day,preferably to be taken in the evening with meal.

The present invention further provides a DPP-4 inhibitor as definedherein for use in (add-on or initial) combination therapy with metformin(e.g. in a total daily amount from 500 to 2000 mg metforminhydrochloride, such as e.g. 500 mg, 850 mg or 1000 mg once or twicedaily).

With respect to embodiment B, the methods of synthesis for the DPP-4inhibitors of embodiment B are described in the scientific literatureand/or in published patent documents, particularly in those citedherein.

Suitable doses and dosage forms of the DPP-4 inhibitors may bedetermined by a person skilled in the art and may include thosedescribed herein or in the relevant references.

For pharmaceutical application in warm-blooded vertebrates, particularlyhumans, the compounds of this invention are usually used in dosages from0.001 to 100 mg/kg body weight, preferably at 0.1-15 mg/kg, in each case1 to 4 times a day. For this purpose, the compounds, optionally combinedwith other active substances, may be incorporated together with one ormore inert conventional carriers and/or diluents, e.g. with corn starch,lactose, glucose, microcrystalline cellulose, magnesium stearate,polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,water/glycerol, water/sorbitol, water/polyethylene glycol, propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substancessuch as hard fat or suitable mixtures thereof into conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions or suppositories.

The pharmaceutical compositions according to this invention comprisingthe DPP-4 inhibitors as defined herein are thus prepared by the skilledperson using pharmaceutically acceptable formulation excipients asdescribed in the art. Examples of such excipients include, without beingrestricted to diluents, binders, carriers, fillers, lubricants, flowpromoters, crystallisation retardants, disintegrants, solubilizers,colorants, pH regulators, surfactants and emulsifiers.

Examples of suitable diluents for compounds according to embodiment Ainclude cellulose powder, calcium hydrogen phosphate, erythritol, lowsubstituted hydroxypropyl cellulose, mannitol, pregelatinized starch orxylitol.

Examples of suitable lubricants for compounds according to embodiment Ainclude talc, polyethyleneglycol, calcium behenate, calcium stearate,hydrogenated castor oil or magnesium stearate.

Examples of suitable binders for compounds according to embodiment Ainclude copovidone (copolymerisates of vinylpyrrolidon with othervinylderivates), hydroxypropyl methylcellulose (HPMC),hydroxypropylcellulose (HPC), polyvinylpyrrolidon (povidone),pregelatinized starch, or low-substituted hydroxypropylcellulose(L-HPC).

Examples of suitable disintegrants for compounds according to embodimentA include corn starch or crospovidone.

Suitable methods of preparing pharmaceutical formulations of the DPP-4inhibitors according to embodiment A of the invention are

-   -   direct tabletting of the active substance in powder mixtures        with suitable tabletting excipients;    -   granulation with suitable excipients and subsequent mixing with        suitable excipients and subsequent tabletting as well as film        coating; or    -   packing of powder mixtures or granules into capsules.

Suitable granulation methods are

-   -   wet granulation in the intensive mixer followed by fluidised bed        drying;    -   one-pot granulation;    -   fluidised bed granulation; or    -   dry granulation (e.g. by roller compaction) with suitable        excipients and subsequent tabletting or packing into capsules.

An exemplary composition (e.g. tablet core) of a DPP-4 inhibitoraccording to embodiment A of the invention comprises the first diluentmannitol, pregelatinized starch as a second diluent with additionalbinder properties, the binder copovidone, the disintegrant corn starch,and magnesium stearate as lubricant; wherein copovidone and/or cornstarch may be optional.

A tablet of a DPP-4 inhibitor according to embodiment A of the inventionmay be film coated, preferably the film coat compriseshydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), talc,titanium dioxide and iron oxide (e.g. red and/or yellow).

For details on dosage forms, formulations and administration of DPP-4inhibitors of this invention and/or GLP-1 receptor agonists of thisinvention, reference is made to scientific literature and/or publishedpatent documents, particularly to those cited herein.

In a preferred embodiment the element DPP-4 inhibitor of the combinationaccording to the invention is preferably administered orally. In anotherpreferred embodiment the component GLP-1 receptor agonist of thecombination is preferably administered by injection.

Injectable formulations of the GLP-1 receptor agonists of this inventionmay be prepared according to known formulation techniques, e.g. usingsuitable liquid carriers, which usually comprise sterile water, and,optionally, further additives e.g. for aiding solubility or forpreservation or the like, to obtain injectable solutions or suspensions.

The pharmaceutical compositions (or formulations) may be packaged in avariety of ways. Generally, an article for distribution includes acontainer that contains the pharmaceutical composition in an appropriateform. Tablets are typically packed in an appropriate primary package foreasy handling, distribution and storage and for assurance of properstability of the composition at prolonged contact with the environmentduring storage. Primary containers for tablets may be bottles or blisterpacks.

A suitable bottle, e.g. for a pharmaceutical composition or combinationcomprising a DPP-4 inhibitor according to embodiment A of the invention,may be made from glass or polymer (preferably polypropylene (PP) or highdensity polyethylene (HD-PE)) and sealed with a screw cap. The screw capmay be provided with a child resistant safety closure (e.g.press-and-twist closure) for preventing or hampering access to thecontents by children. If required (e.g. in regions with high humidity),by the additional use of a desiccant (such as e.g. bentonite clay,molecular sieves, or, preferably, silica gel) the shelf life of thepackaged composition can be prolonged.

A suitable blister pack, e.g. for a pharmaceutical composition orcombination comprising a DPP-4 inhibitor according to embodiment A ofthe invention, comprises or is formed of a top foil (which is breachableby the tablets) and a bottom part (which contains pockets for thetablets). The top foil may contain a metalic foil, particularly analuminium or aluminium alloy foil (e.g. having a thickness of 20 μm to45 μm, preferably 20 μm to 25 μm) that is coated with a heat-sealingpolymer layer on its inner side (sealing side). The bottom part maycontain a multi-layer polymer foil (such as e.g. poly(vinyl chloride)(PVC) coated with poly(vinylidene chloride) (PVDC); or a PVC foillaminated with poly(chlorotrifluoroethylene) (PCTFE)) or a multi-layerpolymer-metal-polymer foil (such as e.g. a cold-formable laminatedPVC/aluminium/polyamide composition).

To ensure a long storage period especially under hot and wet climateconditions an additional overwrap or pouch made of a multi-layerpolymer-metal-polymer foil (e.g. a laminatedpolyethylen/aluminium/polyester composition) may be used for the blisterpacks. Supplementary desiccant (such as e.g. bentonite clay, molecularsieves, or, preferably, silica gel) in this pouch package may prolongthe shelf life even more under such harsh conditions.

The article may further comprise a label or package insert, which referto instructions customarily included in commercial packages oftherapeutic products, that may contain information about theindications, usage, dosage, administration, contraindications and/orwarnings concerning the use of such therapeutic products. In oneembodiment, the label or package inserts indicates that the compositioncan be used for any of the purposes described herein.

With respect to the first embodiment (embodiment A), the dosagetypically required of the DPP-4 inhibitors mentioned herein inembodiment A when administered intravenously is 0.1 mg to 10 mg,preferably 0.25 mg to 5 mg, and when administered orally is 0.5 mg to100 mg, preferably 2.5 mg to 50 mg or 0.5 mg to 10 mg, more preferably2.5 mg to 10 mg or 1 mg to 5 mg, in each case 1 to 4 times a day. Thus,e.g. the dosage of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinewhen administered orally is 0.5 mg to 10 mg per patient per day,preferably 2.5 mg to 10 mg or 1 mg to 5 mg per patient per day.

A dosage form prepared with a pharmaceutical composition comprising aDPP-4 inhibitor mentioned herein in embodiment A contain the activeingredient in a dosage range of 0.1-100 mg. Thus, e.g. particular dosagestrengths of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineare 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg.

With respect to the second embodiment (embodiment B), the doses of DPP-4inhibitors mentioned herein in embodiment B to be administered tomammals, for example human beings, of, for example, approximately 70 kgbody weight, may be generally from about 0.5 mg to about 350 mg, forexample from about 10 mg to about 250 mg, preferably 20-200 mg, morepreferably 20-100 mg, of the active moiety per person per day, or fromabout 0.5 mg to about 20 mg, preferably 2.5-10 mg, per person per day,divided preferably into 1 to 4 single doses which may, for example, beof the same size. Single dosage strengths comprise, for example, 10, 25,40, 50, 75, 100, 150 and 200 mg of the DPP-4 inhibitor active moiety.

A dosage strength of the DPP-4 inhibitor sitagliptin is usually between25 and 200 mg of the active moiety. A recommended dose of sitagliptin is100 mg calculated for the active moiety (free base anhydrate) oncedaily. Unit dosage strengths of sitagliptin free base anhydrate (activemoiety) are 25, 50, 75, 100, 150 and 200 mg. Particular unit dosagestrengths of sitagliptin (e.g. per tablet) are 25, 50 and 100 mg. Anequivalent amount of sitagliptin phosphate monohydrate to thesitagliptin free base anhydrate is used in the pharmaceuticalcompositions, namely, 32.13, 64.25, 96.38, 128.5, 192.75, and 257 mg,respectively. Adjusted dosages of 25 and 50 mg sitagliptin are used forpatients with renal failure. Typical dosage strengths of the dualcombination of sitagliptin/metformin are 50/500 mg and 50/1000 mg.

A dosage range of the DPP-4 inhibitor vildagliptin is usually between 10and 150 mg daily, in particular between 25 and 150 mg, 25 and 100 mg or25 and 50 mg or 50 and 100 mg daily.

Particular examples of daily oral dosage are 25, 30, 35, 45, 50, 55, 60,80, 100 or 150 mg. In a more particular aspect, the daily administrationof vildagliptin may be between 25 and 150 mg or between 50 and 100 mg.In another more particular aspect, the daily administration ofvildagliptin may be 50 or 100 mg. The application of the activeingredient may occur up to three times a day, preferably one or twotimes a day. Particular dosage strengths are 50 mg or 100 mgvildagliptin. Typical dosage strengths of the dual combination ofvildagliptin/metformin are 50/850 mg and 50/1000 mg.

Alogliptin may be administered to a patient at a daily dose of between 5mg/day and 250 mg/day, optionally between 10 mg and 200 mg, optionallybetween 10 mg and 150 mg, and optionally between 10 mg and 100 mg ofalogliptin (in each instance based on the molecular weight of the freebase form of alogliptin). Thus, specific dosage amounts that may be usedinclude, but are not limited to 10 mg, 12.5 mg, 20 mg, 25 mg, 50 mg, 75mg and 100 mg of alogliptin per day. Alogliptin may be administered inits free base form or as a pharmaceutically acceptable salt.

Saxagliptin may be administered to a patient at a daily dose of between2.5 mg/day and 100 mg/day, optionally between 2.5 mg and 50 mg. Specificdosage amounts that may be used include, but are not limited to 2.5 mg,5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg and 100 mg of saxagliptinper day. Typical dosage strengths of the dual combination ofsaxagliptin/metformin are 2.5/500 mg and 2.5/1000 mg.

A special embodiment of the DPP-4 inhibitors of this invention refers tothose orally administered DPP-4 inhibitors which are therapeuticallyefficacious at low dose levels, e.g. at oral dose levels<100 mg or <70mg per patient per day, preferably <50 mg, more preferably <30 mg or <20mg, even more preferably from 1 mg to 10 mg, particularly from 1 mg to 5mg (more particularly 5 mg), per patient per day (if required, dividedinto 1 to 4 single doses, particularly 1 or 2 single doses, which may beof the same size, preferentially, administered orally once- or twicedaily (more preferentially once-daily), advantageously, administered atany time of day, with or without food. Thus, for example, the daily oralamount 5 mg BI 1356 can be given in an once daily dosing regimen (i.e. 5mg BI 1356 once daily) or in a twice daily dosing regimen (i.e. 2.5 mgBI 1356 twice daily), at any time of day, with or without food.

The GLP-1 receptor agonist is typically administered by subcutaneousinjection, e.g. ranging from thrice daily, twice daily, once daily toonce weekly injection. Suitable doses and dosage forms of the GLP-1receptor agonist may be determined by a person skilled in the art.

For example, exenatide is administered twice daily by subcutaneousinjection (Byetta, 5-30 μg, particularly 5-20μg, preferably 5-10 μg,specific dosage strengths are 5 or 10 μg) before a main meal.

Exenatide LAR is administered once weekly by subcutaneous injection(0.1-3 mg, particularly 0.5 mg to 2.0 mg, specific dosage strengths are0.8 mg or 2.0 mg).

Liraglutide is administered once daily by subcutaneous injection(Victoza, 0.5-3 mg, particularly 0.5 mg to 2 mg, specific dosagestrengths are 0.6 mg, 0.9 mg, 1.2 mg or 1.8 mg).

Taspoglutide is administered once weekly by subcutaneous injection (1-30mg, specific dosage strengths are 1 mg, 8 mg, 10 mg, 20 mg or 30 mg).

Semaglutide is administered once weekly by subcutaneous injection(0.1-1.6 mg).

Albiglutide is administered once weekly by subcutaneous injection (4-30mg, specific dosage strengths are 4 mg, 15 mg or 30 mg).

Lixisenatide is administered once daily by subcutaneous injection (10-20μg, specific dosage strengths are 10 μg, 15 μg or 20 μg).

Dulaglutide is administered once weekly by subcutaneous injection(0.25-3 mg, specific dosage strengths are 0.25 mg, 0.5 mg, 0.75 mg, 1.0mg, 1.5 mg, 2.0 mg or 3.0 mg).

Besides delivery by injection, other routes of administration of GLP-1receptor agonists may be contemplated, for example, GLP-1 receptoragonists for use in combination therapy within the meaning of thisinvention also include, without being limited, such ones which aresuited and/or formulated for oral delivery, continuous (subcutaneous)delivery, pulmonary (e.g. via inhalation) or nasal delivery, ortransdermal delivery (e.g. via patch), with subcutaneous injection beingpreferred.

The dosage of the active ingredients in the combinations andcompositions in accordance with the present invention may be varied,although the amount of the active ingredients shall be such that asuitable dosage form is obtained. Hence, the selected dosage and theselected dosage form shall depend on the desired therapeutic effect, theroute of administration and the duration of the treatment. Suitabledosage ranges for the combination are from the maximal tolerated dosefor the single agent to lower doses, e.g. to one tenth of the maximaltolerated dose.

A particularly preferred DPP-4 inhibitor to be emphasized within themeaning of this invention is1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine(also known as BI 1356 or linagliptin). BI 1356 exhibits high potency,24 h duration of action, and a wide therapeutic window. In patients withtype 2 diabetes receiving multiple oral doses of 1, 2.5, 5 or 10 mg ofBI 1356 once daily for 12 days, BI 1356 shows favourable pharmacodynamicand pharmacokinetic profile (see e.g. Table i below) with rapidattainment of steady state (e.g. reaching steady state plasma levels(>90% of the pre-dose plasma concentration on Day 13) between second andfifth day of treatment in all dose groups), little accumulation (e.g.with a mean accumulation ratio R_(A,AUC)≦1.4 with doses above 1 mg) andpreserving a long-lasting effect on DPP-4 inhibition (e.g. with almostcomplete (>90%) DPP-4 inhibition at the 5 mg and 10 mg dose levels, i.e.92.3 and 97.3% inhibition at steady state, respectively, and >80%inhibition over a 24 h interval after drug intake), as well assignificant decrease in 2 h postprandial blood glucose excursions by 80%(already on Day 1) in doses 2.5 mg, and with the cumulative amount ofunchanged parent compound excreted in urine on Day 1 being below 1% ofthe administered dose and increasing to not more than about 3-6% on Day12 (renal clearance CL_(R,ss) is from about 14 to about 70 mL/min forthe administered oral doses, e.g. for the 5 mg dose renal clearance isabout 70 ml/min). In people with type 2 diabetes BI 1356 shows aplacebo-like safety and tolerability. With low doses of about 5 mg, BI1356 acts as a true once-daily oral drug with a full 24 h duration ofDPP-4 inhibition. At therapeutic oral dose levels, BI 1356 is mainlyexcreted via the liver and only to a minor extent (about <7% of theadministered oral dose) via the kidney. BI 1356 is primarily excretedunchanged via the bile. The fraction of BI 1356 eliminated via thekidneys increases only very slightly over time and with increasing dose,so that there will likely be no need to modify the dose of BI 1356 basedon the patients' renal function. The non-renal elimination of BI 1356 incombination with its low accumulation potential and broad safety marginmay be of significant benefit in a patient population that has a highprevalence of renal insufficiency and diabetic nephropathy.

TABLE i Geometric mean (gMean) and geometric coefficient of variation(gCV) of pharmacokinetic parameters of BI 1356 at steady state (Day 12)1 mg 2.5 mg 5 mg 10 mg Parameter gMean (gCV) gMean (gCV) gMean (gCV)gMean (gCV) AUC₀₋₂₄ 40.2 (39.7) 85.3 (22.7)  118 (16.0)  161 (15.7)[nmol · h/L] AUC_(T,SS) 81.7 (28.3)  117 (16.3)  158 (10.1)  190 (17.4)[nmol · h/L] C_(max) 3.13 (43.2) 5.25 (24.5) 8.32 (42.4) 9.69 (29.8)[nmol/L] C_(max,ss) 4.53 (29.0) 6.58 (23.0) 11.1 (21.7) 13.6 (29.6)[nmol/L] t_(max)* [h] 1.50 2.00 1.75 2.00 [1.00-3.00] [1.00-3.00][0.92-6.02] [1.50-6.00] t_(max,ss)* [h] 1.48 1.42 1.53 1.34 [1.00-3.00][1.00-3.00] [1.00-3.00] [0.50-3.00] T_(1/2,ss) [h]  121 (21.3)  113(10.2) 131 (17.4)  130 (11.7) Accumu- 23.9 (44.0) 12.5 (18.2) 11.4(37.4) 8.59 (81.2) lation t_(1/2,) [h] R_(A,Cmax) 1.44 (25.6) 1.25(10.6) 1.33 (30.0) 1.40 (47.7) R_(A,AUC) 2.03 (30.7) 1.37 (8.2)  1.33(15.0) 1.18 (23.4) fe₀₋₂₄ [%] NC 0.139 (51.2)  0.453 (125)   0.919(115)   fe_(T,SS) [%] 3.34 (38.3) 3.06 (45.1) 6.27 (42.2) 3.22 (34.2)CL_(R,ss) 14.0 (24.2) 23.1 (39.3)   70 (35.0) 59.5 (22.5) [mL/min]*median and range [min-max] NC not calculated as most values below lowerlimit of quantification

As different metabolic functional disorders often occur simultaneously,it is quite often indicated to combine a number of different activeprinciples with one another. Thus, depending on the functional disordersdiagnosed, improved treatment outcomes may be obtained if a DPP-4inhibitor is combined with active substances customary for therespective disorders, such as e.g. one or more active substancesselected from among the other antidiabetic substances, especially activesubstances that lower the blood sugar level or the lipid level in theblood, raise the HDL level in the blood, lower blood pressure or areindicated in the treatment of atherosclerosis or obesity.

The DPP-4 inhibitors mentioned above—besides their use inmono-therapy—may also be used in conjunction with other activesubstances, by means of which improved treatment results can beobtained. Such a combined treatment may be given as a free combinationof the substances or in the form of a fixed combination, for example ina tablet or capsule. Pharmaceutical formulations of the combinationpartner needed for this may either be obtained commercially aspharmaceutical compositions or may be formulated by the skilled manusing conventional methods. The active substances which may be obtainedcommercially as pharmaceutical compositions are described in numerousplaces in the prior art, for example in the list of drugs that appearsannually, the “Rote Liste®” of the federal association of thepharmaceutical industry, or in the annually updated compilation ofmanufacturers' information on prescription drugs known as the“Physicians' Desk Reference”.

Examples of antidiabetic combination partners are metformin;sulphonylureas such as glibenclamide, tolbutamide, glimepiride,glipizide, gliquidon, glibornuride and gliclazide; nateglinide;repaglinide; mitiglinide, thiazolidinediones such as rosiglitazone andpioglitazone; PPAR gamma modulators such as metaglidases; PPAR-gammaagonists such as mitoglitazone, INT-131, balaglitazone or rivoglitazone;PPAR-gamma antagonists; PPAR-gamma/alpha modulators such astesaglitazar, muraglitazar, aleglitazar, indeglitazar and KRP297;PPAR-gamma/alpha/delta modulators such as e.g. lobeglitazone;AMPK-activators such as AICAR; acetyl-CoA carboxylase (ACC1 and ACC2)inhibitors; diacylglycerol-acetyltransferase (DGAT) inhibitors;pancreatic beta cell GCRP agonists such as SMT3-receptor-agonists andGPR119, such as the GPR119 agonists5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidineor5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-2-(4-methanesulfonyl-phenyl)-pyridine;11β-HSD-inhibitors; FGF19 agonists or analogues; alpha-glucosidaseblockers such as acarbose, voglibose and miglitol; alpha2-antagonists;insulin and insulin analogues such as human insulin, insulin lispro,insulin glusilin, r-DNA-insulinaspart, NPH insulin, insulin detemir,insulin degludec, insulin tregopil, insulin zinc suspension and insulinglargin; Gastric inhibitory Peptide (GIP); amylin and amylin analogues(e.g. pramlintide or davalintide); GLP-1 and GLP-1 analogues such asExendin-4, e.g. exenatide, exenatide LAR, liraglutide, taspoglutide,lixisenatide (AVE-0010), LY-2428757 (a PEGylated version of GLP-1),dulaglutide (LY-2189265), semaglutide or albiglutide; SGLT2-inhibitorssuch as e.g. dapagliflozin, sergliflozin (KGT-1251), atigliflozin,canagliflozin or(1S)-1,5-anhydro-1-[3-(1-benzothiophen-2-ylmethyl)-4-fluorophenyl]-D-glucitol,ipragliflozin, tofogliflozin, luseogliflozin; inhibitors of proteintyrosine-phosphatase (e.g. trodusquemine); inhibitors ofglucose-6-phosphatase; fructose-1,6-bisphosphatase modulators; glycogenphosphorylase modulators; glucagon receptor antagonists;phosphoenolpyruvatecarboxykinase (PEPCK) inhibitors; pyruvatedehydrogenasekinase (PDK) inhibitors; inhibitors of tyrosine-kinases (50mg to 600 mg) such as PDGF-receptor-kinase (cf. EP-A-564409, WO98/35958, US 5093330, WO 2004/005281, and WO 2006/041976) or ofserine/threonine kinases; glucokinase/regulatory protein modulatorsincl. glucokinase activators; glycogen synthase kinase inhibitors;inhibitors of the SH2-domain-containing inositol 5-phosphatase type 2(SHIP2); IKK inhibitors such as high-dose salicylate; JNK1 inhibitors;protein kinase C-theta inhibitors; beta 3 agonists such as ritobegron,YM 178, solabegron, talibegron, N-5984, GRC-1087, rafabegron, FMP825;aldosereductase inhibitors such as AS 3201, zenarestat, fidarestat,epalrestat, ranirestat, NZ-314, CP-744809, and CT-112; SGLT-1 or SGLT-2inhibitors; KV 1.3 channel inhibitors; GPR40 modulators such as e.g.[(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]aceticacid; SCD-1 inhibitors; CCR-2 antagonists; dopamine receptor agonists(bromocriptine mesylate [Cycloset]);4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutanoic acid; sirtuinstimulants; and other DPP IV inhibitors.

Metformin is usually given in doses varying from about 500 mg to 2000 mgup to 2500 mg per day using various dosing regimens from about 100 mg to500 mg or 200 mg to 850 mg (1-3 times a day), or about 300 mg to 1000 mgonce or twice a day, or delayed-release metformin in doses of about 100mg to 1000 mg or preferably 500 mg to 1000 mg once or twice a day orabout 500 mg to 2000 mg once a day. Particular dosage strengths may be250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride.

For children 10 to 16 years of age, the recommended starting dose ofmetformin is 500 mg given once daily. If this dose fails to produceadequate results, the dose may be increased to 500 mg twice daily.Further increases may be made in increments of 500 mg weekly to amaximum daily dose of 2000 mg, given in divided doses (e.g. 2 or 3divided doses). Metformin may be administered with food to decreasenausea.

A dosage of pioglitazone is usually of about 1-10 mg, 15 mg, 30 mg, or45 mg once a day.

Rosiglitazone is usually given in doses from 4 to 8 mg once (or dividedtwice) a day (typical dosage strengths are 2, 4 and 8 mg).

Glibenclamide (glyburide) is usually given in doses from 2.5-5 to 20 mgonce (or divided twice) a day (typical dosage strengths are 1.25, 2.5and 5 mg), or micronized glibenclamide in doses from 0.75-3 to 12 mgonce (or divided twice) a day (typical dosage strengths are 1.5, 3, 4.5and 6 mg).

Glipizide is usually given in doses from 2.5 to 10-20 mg once (or up to40 mg divided twice) a day (typical dosage strengths are 5 and 10 mg),or extended-release glibenclamide in doses from 5 to 10 mg (up to 20 mg)once a day (typical dosage strengths are 2.5, 5 and 10 mg).

Glimepiride is usually given in doses from 1-2 to 4 mg (up to 8 mg) oncea day (typical dosage strengths are 1, 2 and 4 mg).

A dual combination of glibenclamide/metformin is usually given in dosesfrom 1.25/250 once daily to 10/1000 mg twice daily. (typical dosagestrengths are 1.25/250, 2.5/500 and 5/500 mg).

A dual combination of glipizide/metformin is usually given in doses from2.5/250 to 10/1000 mg twice daily (typical dosage strengths are 2.5/250,2.5/500 and 5/500 mg).

A dual combination of glimepiride/metformin is usually given in dosesfrom 1/250 to 4/1000 mg twice daily.

A dual combination of rosiglitazone/glimepiride is usually given indoses from 4/1 once or twice daily to 4/2 mg twice daily (typical dosagestrengths are 4/1, 4/2, 4/4, 8/2 and 8/4 mg).

A dual combination of pioglitazone/glimepiride is usually given in dosesfrom 30/2 to 30/4 mg once daily (typical dosage strengths are 30/4 and45/4 mg).

A dual combination of rosiglitazone/metformin is usually given in dosesfrom 1/500 to 4/1000 mg twice daily (typical dosage strengths are 1/500,2/500, 4/500, 2/1000 and 4/1000 mg).

A dual combination of pioglitazone/metformin is usually given in dosesfrom 15/500 once or twice daily to 15/850 mg thrice daily (typicaldosage strengths are 15/500 and 15/850 mg).

The non-sulphonylurea insulin secretagogue nateglinide is usually givenin doses from 60 to 120 mg with meals (up to 360 mg/day, typical dosagestrengths are 60 and 120 mg); repaglinide is usually given in doses from0.5 to 4 mg with meals (up to 16 mg/day, typical dosage strengths are0.5, 1 and 2 mg). A dual combination of repaglinide/metformin isavailable in dosage strengths of 1/500 and 2/850 mg.

Acarbose is usually given in doses from 25 to 100 mg with meals.Miglitol is usually given in doses from 25 to 100 mg with meals.

Examples of combination partners that lower the lipid level in the bloodare HMG-CoA-reductase inhibitors such as simvastatin, atorvastatin,lovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin;fibrates such as bezafibrate, fenofibrate, clofibrate, gemfibrozil,etofibrate and etofyllinclofibrate; nicotinic acid and the derivativesthereof such as acipimox; PPAR-alpha agonists; PPAR-delta agonists suchas e.g.{4-[(R)-2-ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid; inhibitors of acyl-coenzyme A:cholesterolacyltransferase (ACAT; EC2.3.1.26) such as avasimibe; cholesterol resorption inhibitors such asezetimib; substances that bind to bile acid, such as cholestyramine,colestipol and colesevelam; inhibitors of bile acid transport; HDLmodulating active substances such as D4F, reverse D4F, LXR modulatingactive substances and FXR modulating active substances; CETP inhibitorssuch as torcetrapib, JTT-705 (dalcetrapib) or compound 12 from WO2007/005572 (anacetrapib); LDL receptor modulators; MTP inhibitors (e.g.lomitapide); and ApoB100 antisense RNA.

A dosage of atorvastatin is usually from 1 mg to 40 mg or 10 mg to 80 mgonce a day.

Examples of combination partners that lower blood pressure arebeta-blockers such as atenolol, bisoprolol, celiprolol, metoprolol andcarvedilol; diuretics such as hydrochlorothiazide, chlortalidon,xipamide, furosemide, piretanide, torasemide, spironolactone,eplerenone, amiloride and triamterene; calcium channel blockers such asamlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine,felodipine, lacidipine, lercanipidine, manidipine, isradipine,nilvadipine, verapamil, gallopamil and diltiazem; ACE inhibitors such asramipril, lisinopril, cilazapril, quinapril, captopril, enalapril,benazepril, perindopril, fosinopril and trandolapril; as well asangiotensin II receptor blockers (ARBs) such as telmisartan,candesartan, valsartan, losartan, irbesartan, olmesartan, azilsartan andeprosartan.

A dosage of telmisartan is usually from 20 mg to 320 mg or 40 mg to 160mg per day.

Examples of combination partners which increase the HDL level in theblood are Cholesteryl Ester Transfer Protein (CETP) inhibitors;inhibitors of endothelial lipase; regulators of ABC1; LXRalphaantagonists; LXRbeta agonists; PPAR-delta agonists; LXRalpha/betaregulators, and substances that increase the expression and/or plasmaconcentration of apolipoprotein A-I.

Examples of combination partners for the treatment of obesity aresibutramine; tetrahydrolipstatin (orlistat); alizyme (cetilistat);dexfenfluramine; axokine; cannabinoid receptor 1 antagonists such as theCB1 antagonist rimonobant; MCH-1 receptor antagonists; MC4 receptoragonists; NPY5 as well as NPY2 antagonists (e.g. velneperit); beta3-ARagonists such as SB-418790 and AD-9677; 5HT2c receptor agonists such asAPD 356 (lorcaserin); myostatin inhibitors; Acrp30 and adiponectin;steroyl CoA desaturase (SCD1) inhibitors; fatty acid synthase (FAS)inhibitors; CCK receptor agonists; Ghrelin receptor modulators; Pyy3-36; orexin receptor antagonists; and tesofensine; as well as the dualcombinations bupropion/naltrexone, bupropion/zonisamide,topiramate/phentermine and pramlintide/metreleptin.

Examples of combination partners for the treatment of atherosclerosisare phospholipase A2 inhibitors; inhibitors of tyrosine-kinases (50 mgto 600 mg) such as PDGF-receptor-kinase (cf. EP-A-564409, WO 98/35958,US 5093330, WO 2004/005281, and WO 2006/041976); oxLDL antibodies andoxLDL vaccines; apoA-1 Milano; ASA; and VCAM-1 inhibitors.

The present invention is not to be limited in scope by the specificembodiments described herein. Various modifications of the invention inaddition to those described herein may become apparent to those skilledin the art from the present disclosure. Such modifications are intendedto fall within the scope of the appended claims.

All patent applications cited herein are hereby incorporated byreference in their entireties.

Further embodiments, features and advantages of the present inventionmay become apparent from the following examples. The following examplesserve to illustrate, by way of example, the principles of the inventionwithout restricting it.

EXAMPLES

The aim of this study is to evaluate the effects of repeatedadministration of a GLP-1 receptor agonist, such as e.g. exenatide (30μg/kg/day sc) by subcutaneous minipump for 10 or 28 days and exenatide(30 μg/kg/day sc) for 10 days followed by vehicle or BI 1356 (3 mg/kgpo) given orally on body weight in dietary-induced obese (DIO) femaleWistar rats (ie in an animal model of obesity). BI 1356 is a novelcompound with potential for the treatment of obesity/diabetes. Allexperimental procedures concerning the use of laboratory animals arecarried out under a Home Office Certificate of Designation.

Methodology:

Obesity is induced-in female Wistar rats for 20 weeks by giving theanimals free access to powdered high fat diet (VRF1 plus 20% lard),ground chocolate, ground peanuts and tap water at all times. Two weeksbefore the start of the baseline readings, animals are housed singly inpolypropylene cages with wire grid floors to enable the food intake ofeach rat to be recorded. Following a 5-day baseline period, osmoticminipumps (2ML2) delivering either vehicle or exenatide are implantedsubcutaneously (sc) under anaesthetic. The surgery is performed over twodays and therefore the study was divided into two arms (staggered by oneday) and the data pooled. On day 11, the osmotic minipumps are removedfrom all animals and replaced with a new pump (2ML4) containing vehicleor exenatide for 10 days. In addition animals are treated orally witheither vehicle (0.5% Natrosol) or BI 1356 and body weight is recordeddaily as shown in FIG. 1.

When the osmotic mini-pumps start to emerge through the wound clips,animals are re-clipped on one occasion per animal only. Rats are removedfrom the feeding laboratory for approximately 30 min and the woundresealed under brief (˜10 min) anaesthesia. If the wound re-opened therat is terminated.

Results: Exenatide leads to significant weight loss during the first 11days. When the animals receive vehicle+vehicle from day 11 on, they gainweight again. However, the animals treated further with the DPP 4inhibitor BI 1356 stabilize their body weight at the new weight leveland are significantly lighter than the vehicle-treated control animals(see FIG. 1).

Specific surgical procedures: Animals are anaesthetised using gaseousanaesthesia (isoflurane). Specifically, anaesthesia is induced withisoflurane (5%), O₂ (2 l/min), N₂O (2 l/min). During this time theimplant site is shaved. All surgery will use aseptic technique.

During surgery, anaesthesia is maintained with isoflurane at 2%, with O₂(1 l/min) and N₂O (1 l/min). The incision is sited at the flank, and apocket of suitable size is created and the pump inserted. Pumps arefilled with vehicle or exenatide shortly before implantation. The woundis sealed by the use of one or more wound clips (VetTech Solutions).Betadine spray and Opsite dressing are applied to the wound. Immediatelypost surgery, the N₂O gas stream is removed and O₂ increased to a flowrate of 2 l/min. After approximately 1 min, isoflurane is turned off.Once animals begin to show signs of recovery (e.g. faster breathingrate, tail and/or limb movement) they are placed into the home cage on aheat mat with a heat lamp present. Animals are carefully monitored forup to 2 h following surgery and until they are fully recovered. As soonas the rats recover from the anaesthetic they have free access to foodand water.

FIG. 1: Body Weight Development

FIG. 1: Results are adjusted means±sem; n=5-51 (n values in brackets arethe number remaining on day 21.) SEMs are calculated from the residualsof the statistical model. Data analysed by ANCOVA with body weight onDay 1 as covariate. Multiple comparisons versus the vehicle controlgroup are by multiple t test. Significant differences from vehiclecontrol: *p<0.05, **p<0.01, *** p<0.001. Significant differences fromExenatide 30 μg/kg/day (Day 1-10)+vehicle (from Day 11): #p<0.05,##p<0.01 (multiple t test). Percent values are weight loss compared toVehicle on Day 21.

Exenatide-treated animals show higher incidence for skin alterations,which lead often to euthanization of the respective animals.Linagliptin-treated animals show better survival (see FIG. 2, e.g. afterabout 22-23 days treatment, vehicle treated animals (A) show about 65%survival, exenatide+vehicle-treated animals (B) show about 67% survival,exenatide+BI 1356-treated animals (E) show about 75% survival, andexenatide-treated animals (F) show about 45% survival).

FIG. 2: Survival Plots

FIG. 3: Linagliptin Attenuates Rebound Of Body Weight (Including BodyFat) Gain Following Discontinuation of glp-1r agonist (e.g. Exendin-4)Treatment

FIG. 3: Results are mean change in body weight of obese female Wistarrats treated with exenatide for either a 10 or 21 day period (n=5-11;Day 1-11 data with exenatide are pooled and include all data for animalstreated with exenatide over this period). Means are adjusted fordifferences between the body weights of the different treatment groupsat baseline (Day 1). SEMs are calculated from the residuals of thestatistical model. On day 11, the mini-pump was removed and replacedwith a second mini-pump. Animals treated with exenatide for 10 days wereswitched to vehicle treatment for the rest of the study. The change inbody weight of animals treated with the DPP-4 inhibitor, linagliptin (3mg/kg po), on exenatide withdrawal are illustrated on the figure (firstbar from right: Exenatide; second bar from right: Exenatide followed byLinagliptin; third bar from right: Exenatide followed by Vehicle).Multiple comparisons versus the vehicle control group were by themultiple t test. Significant differences from vehicle control: *p<0.05;**p<0.01. Significant differences from Exenatide 30 μg/kg/day (Day1-10)+vehicle s.c. and p.o. (from Day 11): #p=0.07 (multiple t test).

FIG. 4: GLP-1R agonist (e.g. Exendin-4) Cessation And Replacement WithLinagliptin Prevents Body Fat Weight Regain

TABLE (a) Carcass composition and final body weight (prior to tissuedissection) of animals at the study conclusion Final Weight Water (g)Fat (g) Protein (g) (g) Mean SEM Mean SEM Mean SEM Mean SEM Vehicle (Day1-10) + 204.2 5.3 123.0 6.5 62.7 1.4 438.2 4.6 Vehicle (from Day 11);Vehicle po from Day 11 Exenatide 30 μg/kg/day 194.6 4.3 132.0 6.3 59.71.8 424.4 4.5 (Day 1-10) + Vehicle (from Day 11); Vehicle po from Day 11Exenatide 30 μg/kg/day 198.0 4.4 117.6 5.0 61.6 2.1 419.1 5.7 (Day1-10) + Vehicle (from Day 11); linagliptin 3 mg/kg po from Day 11Exenatide 30 μg/kg/day 202.1 5.2 103.9 7.5 *$$ 61.4 1.5 410.5 8.3 (Day1-10) + Exenatide (30 μg/kg/day from Day 11); Table (a): Table detailingthe carcass composition and final body weight (prior to tissuedissection) of animals at the study conclusion, n = 6-10. Data areadjusted for differences between treatment groups in body weight atbaseline (Day 1). SEMs are calculated from the residuals of thestatistical model. Comparisons against the control group were by themultiple t test: *p < 0.05. Comparisons against the vehicle-treatedexenatide withdrawal group by multiple t test: $$ p < 0.01.

The effect of linagliptin (BI 1356, 3mg/kg po, once daily for 28 days)either alone or in combination with a low dose of exenatide (3μg/kg/daysc) on body weight, carcass composition and relevant plasma markers ofobese female Wistar rats fed a high-fat cafeteria diet (DIO) rats forapproximately 20 weeks is assessed. Linagliptin has no effect on bodyweight, daily food intake, plasma glucose, insulin or carcass fat in DIOrats compared to vehicle-treated controls and does not augment theeffect of a low dose of exenatide (delivered via a subcutaneouslyimplanted osmotic minipump), when dosed in combination.

In a follow on study (21 days duration), a high dose of exenatide(30μg/kg/day sc) is shown to reduce body weight (6%; p<0.001) and bodyfat (16% p<0.05) in DIO rats compared to vehicle-treated controls.Carcass protein (p=0.8) and water (p=0.7) are not affected. In DIO ratswhere the osmotic minipump delivering exenatide is removed (Day 10) andreplaced by an osmotic minipump delivering saline, weight regain isobserved such that the body weight of these animals is not significantlydifferent to controls (p=0.239) after 21 days. In contrast, linagliptin(3mg/kg po) reduces weight regain after withdrawal of exenatide suchthat a significant difference from controls is evident (p<0.05). Thisweight regain is characterized principally by fat deposition andlinagliptin-treated animals put on 10.6% less fat than vehicle-treatedcounterparts during exenatide withdrawal (p=0.07). In this context,please see also FIG. 3, FIG. 4 and Table (a).

These data demonstrate that linagliptin has no weight reducing effectper se in untreated DIO rats or in DIO rats treated with exenatide butin DIO rats where weight loss is induced by a high dose of a GLP-1receptor agonist or exenatide and then withdrawn, linagliptin reduces ordelays subsequent weight regain. Linagliptin can therefore be used incontrolling weight rebound during intermittent courses of treatment witha GLP-1 receptor agonist or exenatide.

Diabetic patients may switch from one treatment to another in an effortto avoid unpleasant side effects like nausea that are frequentlyreported with a GLP-1 receptor agonist or exenatide treatment.

In conclusion, the present study demonstrates that linagliptin (BI 1356)does not significantly alter body weight, food intake or carcasscomposition in an established and validated animal model of obesity,i.e. drug-naïve female Wistar rats allowed continuous exposure to asimplified three-component cafeteria diet in order to develop markedobesity, insulin resistance (e.g. hyperinsulinaemia) and/or impairedglucose tolerance.

Although exhibiting dietary-induced obesity, the rats used in thepresent studies do not exhibit a diabetic phenotype and, accordingly,their plasma glucose and HbA1c levels are within a normal range.

Accordingly, the present data shows that treatment with linagliptin is auseful strategy for the weight-neutral treatment of diabetes since, incontrast to other drug classes (e.g. thiazolidinediones, sulphonylureas,insulin etc,) linagliptin is unlikely to promote weight gain, a majorcausative factor in the development of diabetes.

Further, the present data are the first to demonstrate thatdietary-induced obese rats treated with exenatide lose weight comparedto vehicle controls but put this weight back on once withdrawn from thedrug. Importantly, this body weight gain does not increase beyond thelevel of vehicle-treated controls and there is evidence that this weightgain, especially the increase in fat, may be reduced by treatment withlinagliptin. Thus, the present invention provides a treatment regimencomprising inducing initial weight loss, e.g. via GLP-1 receptoragonism, and subsequently being replaced by or switching to a DPP-4inhibitor (preferably linagliptin) treatment, which is favourable forreducing, preventing or delaying subsequent weight regain after weightloss, particularly the concomitant increase in body fat.

It is further shown that also the direct combination of linagliptin andlow dose of a GLP-1 receptor agonist (exenatide) has a positive effecton body fat which is greater than for the respective single agents (seeTable (b)).

TABLE b Effect of linagliptin and exenatide combination on plasmaparameters and body composition in DIO rats Day 29 Pump treatment (SC)Exenatide Exenatide Exenatide Vehicle (3 μg/kg/day) (30 μg/kg/day)Vehicle (3 μg/kg/day) Oral treatment Linagliptin Linagliptin (3 mg/kg (3mg/kg Vehicle Vehicle Vehicle PO) PO) Glucose (mM) 8.14 ± 0.33 8.06 ±0.31 7.70 ± 0.21 8.72 ± 0.22 8.51 ± 0.21 Insulin (ng/mL) 2.12 ± 0.341.89 ± 0.32 1.61 ± 0.64 1.82 ± 0.36 1.89 ± 0.31 Leptin (ng/mL) 26.7 ±2.6  20.5 ± 2.3    14.4 ± 1.2^(c)*** 23.9 ± 2.5  21.1 ± 1.6  GLP-1 (pM)3.67 ± 1.1  3.52 ± 0.3  4.58 ± 0.5   5.72 ± 0.9^(b)   5.44 ± 1.3^(b,d )Carcass Protein 60.8 ± 4.6  55.6 ± 5.2  54.3 ± 3.5  63.8 ± 4.0  63.7 ±5.1  (g) Carcass Water 206.8 ± 5.9  209.9 ± 7.7  207.5 ± 3.5  212.6 ±3.42  13.6 ± 3.8  (g) Carcass Fat (g) 161.1 ± 5.9  144.7 ± 10.0  127.3 ±9.3** 151.1 ± 7.3   139.5 ± 7.1^(a)  Table (b): Data are mean ± SEM (n =7-10). Multiple comparisons vs. vehicle are by Williams' test for groupstreated solely with exenatide, and the multiple t test for all othergroups: ^(a)P = 0.050, ^(b)P < 0.05, ^(c)P < 0.001. ^(d)P < 0.05 fromthe exenatide (3 μg/kg/day) group. GLP-1, glucagon-like peptide-1.

These data show that adding linagliptin to a GLP-1 receptor agonist(e.g. exenatide) provides a dose-sparing effect on the use of the GLP-1receptor agonist.

In a further study the efficacy of chronic treatment with linagliptin onbody weight, total body fat, intra-myocellular fat, and hepatic fat in anon-diabetic model of diet induced obesity (DIO) in comparison to theappetite suppressant subutramine is investigated:

Rats are fed a high-fat diet for 3 months and received either vehicle,linagliptin (10 mg/kg), or sibutramine (5 mg/kg) for 6 additional weeks,while continuing the high-fat diet. Magnetic resonance spectroscopy(MRS) analysis of total body fat, muscle fat, and liver fat is performedbefore treatment and at the end of the study.

Sibutramine causes a significant reduction of body weight (−12%) versuscontrol, whereas linagliptin has no significant effect (−3%). Total bodyfat is also significantly reduced by sibutramine (−12%), whereaslinagliptin-treated animals show no significant reduction (−5%).However, linagliptin and sibutramine result both in a potent reductionof intramyocellular fat (−24% and −34%, respectively). In addition,treatment with linagliptin results in a profound decrease of hepatic fat(−39%), whereas the effect of sibutramine (−30%) does not reachsignificance (see Table (c)). Thus, linagliptin is weight neutral butimproves intra-myocellular and hepatic lipid accumulation.

TABLE (c) Effect of linagliptin on body weight total body fat, liver fatand intramyocellular fat Body weight Total body fat Liver fatIntra-myocellular fat % contr. % baseli. % contr. % baseli. % contr. %baseli. % contr. % baseli. Control — +15% —  +11% — +27% — +23% p =0.016 p = 0.001 p = 0.09 p = 0.49 Linagliptin  −3% +12%  −5%   +5% −39%−30% −36% −24% p = 0.56 p = 0.001 p = 0.27 p = 0.06 p = 0.022 p = 0.05 p= 0.14 p = 0.039 Sibutramine −12%  +1% −12% −0.4% −30% −29% −55% −34% p= 0.018 p = 0.64 p = 0.008 p = 0.86 p = 0.13 p = 0.12 p = 0.037 p =0.007

In conclusion, linagliptin treatment provokes a potent reduction ofintramyocellular lipids and hepatic fat, which are both independent ofweight loss. The effects of sibutramine on muscular and hepatic fat areattributed mainly to the known weight reduction induced by thiscompound.

The invention claimed is:
 1. A method for maintaining a subject in astate of reduced weight after weight reducing treatment, said methodcomprising administering linagliptin to said subject, wherein theadministration of linagliptin is carried out subsequent to the weightreducing treatment in order to maintain the reduced body weight or delayan increase in body weight in said subject.
 2. The method according toclaim 1, wherein the weight reducing treatment is selected from diet,exercise and/or treatment with an anti-obesity or weight reducing agentselected from the group consisting of a glucagon-like peptide-1 (GLP-1)receptor agonist, a lipase inhibitor which is orlistat or cetilistat, acannabinoid receptor 1 antagonist, a melanocortin-4 (MC4) receptoragonist, a neuropeptide Y2-receptor (NPY2) antagonist, a5-hydroxytryptamine 2C (5HT2c) receptor agonist, a Ghrelin antagonist,pancreatic peptide YY3-36 (Pyy 3-36), leptin, a diacylglycerolO-acyltransferase 1 (DGAT-1) inhibitor, a noradrenaline-dopamine-5HTreuptake inhibitor, bupropion/naltrexone, bupropion/zonisamide,topiramate/phentermine, pramlintide/metreleptin, a melanin-concentratinghormone (MCH) antagonist, a cholecystokinin (CCK) inhibitor, a fattyacid synthase (FAS) inhibitor, an acetyl-CoA carboxylase (ACC)inhibitor, a stearoyl-CoA desaturase (SCD) inhibitor, a beta3adrenoreceptor agonist, a microsomal triglyceride transfer protein (MTP)inhibitor, and amylin or an amylin analogue which is davalintide orpramlintide.
 3. The method of claim 1, wherein the subject is an obesitypatient prior to weight reducing treatment.
 4. A method for maintaininga subject in a state of reduced weight after weight reducing treatmentwith a GLP-1 receptor agonist selected from exenatide, exenatide LAR,liraglutide, taspoglutide, semaglutide, albiglutide, lixisenatide anddulaglutide, said method comprising administering linagliptin to saidsubject wherein the administration of linagliptin is carried outsubsequent to the weight reducing treatment with said GLP-1 receptoragonist in order to maintain the reduced body weight or delay anincrease in body weight in said subject.